The

The Veterinary Journal 167 (2004) 158–166

Veterinary Journalwww.elsevier.com/locate/tvjl

Prognostic significance of morphological subtypes incanine malignant lymphomas during chemotherapy

Fr�ed�erique Ponce a,b,c,*, Jean-Pierre Magnol c,d, David Ledieu a, Thierry Marchal d,Vanessa Turinelli a, Karine Chalvet-Monfray e, Corinne Fournel-Fleury a

a Hematology-Cytology-Immunology Laboratory, Departement des Animaux de Compagnie, Ecole Nationale V�et�erinaire de Lyon,

1 Avenue Bourgelat, B.P. 83, Marcy L’Etoile 69280, Franceb The Unit of Internal Medicine, Departement des Animaux de Compagnie, Ecole Nationale V�et�erinaire de Lyon,

1 Avenue Bourgelat, B.P. 83, Marcy L’Etoile 69280, Francec The Unit of Oncology, Departement des Animaux de Compagnie, Ecole Nationale V�et�erinaire de Lyon,

1 Avenue Bourgelat, B.P. 83, Marcy L’Etoile 69280, Franced Pathology Laboratory, D�epartment des Animaux de Compagnie, Ecole Nationale V�et�erinaire de Lyon,

1 Avenue Bourgelat, B.P. 83, Marcy L’Etoile 69280, Francee The Unit of Biomathematics and Epidemiology, Ecole Nationale V�et�erinaire de Lyon, Marcy l’Etoile, France

Accepted 6 October 2003

Abstract

The aim of this study was to determine the response of different morphological subtypes of canine lymphoma to a standardized

therapeutic protocol. Diagnosis of lymphoma was based on cytohistological analysis and immunophenotyping with antibodies

against CD3 and CD79a of an enlarged lymph node or an extranodal mass. Fifty-seven cases were classified according to the

updated Kiel classification adapted to the canine species, into 24 B-cell lymphomas (20 centroblastic polymorphic and four Burkitt-

type subtypes), and 33 T-cell lymphomas (10 pleomorphic mixed, 10 lymphoblastic, eight unclassifiable high grade plasmacytoid,

and five small clear-cell subtypes). All dogs were clinically staged at diagnosis. The protocol used LL-asparaginase, vincristine, cy-

clophosphamide, doxorubicin, and prednisone. First remission duration and overall survival time were evaluated. Although the

T-cell phenotype was associated, on the whole, with a poor prognosis, as previously reported in veterinary and human medicine, the

study showed significant prognostic differences between the B- and the T-cell subtypes of canine lymphoma and suggests that cli-

nico-morphological characterization of the disease is justified in dogs, as in humans.

� 2003 Elsevier Ltd. All rights reserved.

Keywords: Dog; Lymphoma; Classification; Oncology; Chemotherapy

1. Introduction

The first studies on non-Hodgkin�s lymphomas

(NHL) in humans showed that the survival of patients

varied from a few months to several years. Furthermore,

the effectiveness of developing therapies clearly varied

with the histological features. Consequently, clinicians

began to demand much more precise and clinically rel-evant histological diagnoses (Harris et al., 1994, 2000;

Solal-Celigny et al., 1997; Armitage, 1999; Isaacson,

* Corresponding author. Tel.: +33-478-872-585; fax: +33-478-872-

617.

E-mail address: f.ponce@vet-lyon.fr (F. Ponce).

1090-0233/$ - see front matter � 2003 Elsevier Ltd. All rights reserved.

doi:10.1016/j.tvjl.2003.10.009

2000; Jaffe et al., 2001). In response to this, the last

classifications of human NHL, the new REAL (Revised

European-American classification of Lymphoid neo-

plasms) (Harris et al., 1994) and WHO (Harris et al.,

2000) classifications, take into account epidemiological,

clinical, morphological, immunophenotypic, and genetic

features and define precise disease entities with their own

prognostic and particular therapeutic schemes (Harris,1999; Jaffe et al., 2001). Therefore, a broad spectrum of

therapeutic options is now available for these different

diseases.

The morphological classifications of canine NHL

have been successively based on the different human

classifications (Breuer and Hermanns, 1998). But, most

F. Ponce et al. / The Veterinary Journal 167 (2004) 158–166 159

of the recent studies, regarding responses to differenttherapeutic protocols and evaluation of prognosis of

NHL have been performed without precise morpho-

logical and immunophenotypical characterization of the

disease, considering canine NHL as a unique entity

(Breuer and Hermanns, 1998; Kiupel et al., 1999; Moore

et al., 2001, 1999; Baskin et al., 2000; Boyce and Kitc-

hell, 2000; Chun et al., 2000). Even if immunophenotype

was determined in some of these therapeutic studies,cytohistological subtypes were never correlated with

survival times (Teske et al., 1994a,b; Starrak et al., 1997;

Kiupel et al., 1999; Chun et al., 2000; Phillips et al.,

2000; Dobson et al., 2001). Only three studies distin-

guished various cytohistological subtypes of B and T

NHL (Teske et al., 1994a,b; Fournel-Fleury et al., 1997,

2002). The most recent took into account the different

clinical presentations along with the different morpho-logical subtypes, in the light of the latest human NHL

classifications (Fournel-Fleury et al., 2002). However,

no therapeutic data were reported.

The aim of the present study was to determine the

response of different morphological subtypes of canine

NHL to a standardized therapeutic protocol and to

address the question whether or not the distinction be-

tween the different subtypes of canine lymphomas, ac-

Table 1

Canine NHL subtypes morphological criteria, according to Fournel-Fleury

B-cell NHL Number

of cases

Histological pattern

Centroblastic

polymorphic

20 Diffuse

Burkitt-typea 4 Diffuse starry-sky

T-cell NHL

Small clear-cell 5 T-zone pattern

Pleomorphic mixed 10 Diffuse

Unclassifiable

high-grade plasmacytoid

8 Diffuse

Lymphoblastic 10 Diffuse

Total 57

MMC, macronucleolated medium-sized-cell.a Burkitt-type on the basis of morphological similarities with the human e

cording to the latest classifications, is clinically justifiedin dogs, as in human medicine.

2. Materials and methods

2.1. Selection of the dogs

One hundred and forty dogs with NHL were pre-sented to the Oncology Unit at the Lyon Veterinary

School between January 1999 and January 2001. Only

dogs without any treatment before diagnosis and with a

complete clinical follow-up during chemotherapy were

included in the study to ensure a population with a

uniform and rigorous protocol. Finally, 57 dogs were

included in this retrospective study.

2.2. Diagnosis and subtypes of NHL (Table 1)

Each diagnosis of NHL was based on the examina-

tion of fine-needle aspirates (FNA) (stained with

May-Gr€unwald-Giemsa) and biopsy specimens (paraf-

fin-embedded sections, stained with haematoxilin and

eosin) from at least one enlarged lymph node or ex-

tranodal mass. In all cases, the immunophenotype was

et al. (1997, 2002)

Cytological criteria Mitotic

index

Mixture of MMC (<20%), small blastic cells

(up to 80%), centroblasts (20–50%), immunoblasts

(<20%)

High

Medium size High

Round nuclei with highly clumped chromatin,

multiple nucleoli

Scant, deeply basophilic cytoplasm, sometimes

vacuolated

Small size Low

Round or slightly irregular nuclei

Extended, unipolar, pale cytoplasm

Small, medium, and large sizes Medium

to high

Irregular nuclei

Pale cytoplasm

Small, medium, and large sizes High

Round or slightly irregular nuclei

Extended, basophilic, plasmacytoid cytoplasm

Medium size High

Round or convoluted nuclei with dusty chromatin

and inconspicuous nucleoli

Poorly extended and basophilic cytoplasm

ntity.

160 F. Ponce et al. / The Veterinary Journal 167 (2004) 158–166

established on fresh or frozen fine-needle aspirates andparaffin-embedded sections, by the use of a polyclonal

antibody against CD3 as a pan-T marker (Ferrer et al.,

1992) and a monoclonal antibody against CD79a as a

pan-B marker (Jones, 1993; Jones et al., 1993). These

procedures have been previously described (Fournel-

Fleury et al., 1997). The cases were classified according

to the updated Kiel classification (Lennert and Feller,

1991) adapted to canine species, and in the light of thecurrent evolution of the human NHL classifications

(REAL and WHO classifications), as previously de-

scribed (Fournel-Fleury et al., 1997, 2002). Samples

were reviewed independently by a cytologist and a

pathologist.

2.3. Clinical staging

All dogs were first evaluated by physical examination,

complete blood count, serum biochemistry, thoracic

radiography, and abdominal ultrasonography. Bone

marrow aspirate was performed in 53 cases, allowing the

dogs to be completely staged at diagnosis according to

the World Health Organization (WHO) V-stage criteria

for canine lymphomas (Owen, 1980). In addition, dogs

were assigned to substage categories of ‘‘a’’ (withoutsystemic signs of illness) or ‘‘b’’ (with systemic signs of

illness) (Fan and Kitchell, 2002).

2.4. Chemotherapy protocol

The combination chemotherapy utilized LL-asparagi-

nase, vincristine, cyclophosphamide, doxorubicin, and

prednisone and was modified from VELCAP protocol(Ogilvie and Moore, 1995). It was maintained until

death. The doses and schedules are provided in Table 3.

The doses of cyclophosphamide were reduced (by 10–

20%) if the dog became neutropenic (<1500 cells/lL).The induction period was defined as the first 5 weeks of

chemotherapy; subsequent treatments were considered

to be maintenance chemotherapy. At first relapse, the

Table 2

Updated Kiel classification of the canine lymphomas (Fournel-Fleury et al.,

(Jaffe et al., 2001) and the domestic animals WHO classification (Valli et al.

Malignant lymphomas

Updated Kiel Human WHO

B-cell neoplasms

Centroblastic polymorphic Diffuse large B-cell lymphoma

Burkitt-type Burkitt lymphoma

T-cell neoplasms

Low-grade malignancy

Small clear-cell (T-zone) Peripheral T-cell lymphoma, unsp

High-grade malignancy

Pleomorphic mixed Peripheral T-cell lymphoma, unsp

Plasmacytoid Peripheral T-cell lymphoma, unsp

Lymphoblastic Precursor T-cell lymphoblastic lym

previous induction protocol was repeated, and the samemaintenance chemotherapy was then applied until the

second relapse. At second relapse, reinduction was

attempted with LL-asparaginase for the first week and

followed by doxorubicin, as the single-agent chemo-

therapy, 3 weeks later and then as a maintenance ther-

apy every 3 weeks, six times in all.

2.5. Assessment of response, first remission duration, and

overall survival time

The response to chemotherapy was evaluated one

week after initiation of treatment. Lymph nodes were

measured with calipers by the same clinician. Complete

response was defined as a 75–100% resolution of lymph

node enlargement and related clinical signs, and nor-

malization of hypercalcaemia. Partial response was de-fined as 50–75% resolution in the largest dimension of

the site of measurable lymphadenopathy and an im-

provement of clinical signs. Stable disease was defined as

0–50% decrease in measurable lymphadenopathy, with

no change in clinical signs. No response was defined as a

further increase of measurable lymphadenopathy, with

or without a worsening of clinical signs (Lucroy et al.,

1998). Dogs were clinically evaluated every 3 weeksduring maintenance therapy. The duration of the first

remission (FR) was defined as the time (in months) be-

tween the start of treatment and the first relapse (re-

currence of lymphadenopathy or extranodal mass

assessed by cytological examination). Overall survival

time (OST) was defined as the time between the start of

treatment and the death of the dog.

2.6. Statistical analysis

First remission and OST curves were estimated by

Kaplan–Meyer statistics for all the different subtypes of

lymphoma and tested using Mantel�s simplified v2 of thelog-rank test (Laplanche et al., 1997; Petrie and Watson,

2000). Probability values p < 0:05 were considered

1997, 2002): possible correlation with the human WHO classification

, 2002)

Domestic animals WHO

Diffuse large B-cell lymphoma

Burkitt-type lymphoma

ecified Not described

ecified Not described

ecified Not described

phoma/leukemia T-cell lymphoblastic leukemia/lymphoma

Table 3

Chemotherapy protocol

Drug name Dose Route Frequency

Five-week induction phase

LL-Asparaginase 400 IU/kg IM Once weekly, on week 1

Vincristine 0.75 mg/m2 IV Once weekly, on weeks 2–5

Cyclophosphamide 250 mg/m2 PO Once weekly, on weeks 2, 5

Prednisone 1 mg/kg PO Once daily

Maintenance phase during remission

Vincristine 0.75 mg/m2 IV Every 3 weeks

Cyclophosphamide 250 mg/m2 PO Every 3 weeks

Prednisone 1 mg/kg PO Every 2 days

Same protocol after first relapse

Induction phase after second relapse

LL-Asparaginase 400 IU/kg IM Once weekly, on week 1

Maintenance phase after second relapse

Doxorubicin 30 mg/m2 IV On week 4, every 3 weeks

IM, intramuscular; IV, intravenous; and PO, per os.

F. Ponce et al. / The Veterinary Journal 167 (2004) 158–166 161

significant for all statistical tests. All statistical analyses

were done with Microsoft Excel 2000.

3. Results

This series of 57 cases included 24 B-cell and 33 T-cellNHL. Six different morphological subtypes of canine

NHL, two subtypes of the B-cell, and four of the T-cell

lineage, entered in this study (Tables 1 and 2). The main

epidemiological, clinical, and survival data are summa-

rized in Tables 4 and 5 for each morphological subtypes.

Among the B-cell NHL, 20 cases were centroblastic

polymorphic and four were Burkitt-type. The centrob-

Table 4

Epidemiological and clinical data of the 57 cases according to morphologica

Morphological

subtypes

Breed Age (years) Sex Ad

La Med Sm M F Gen

CP (20) 17 2 1 7.8 (4–11) 14 6 20

B (4) 4 0 0 8 (7–10) 3 1 4

SCC (5) 3 2 0 8.9 (6–11) 2 3 3

PM (10) 10 0 0 8.4 (5–15) 5 5 10

P (8) 8 0 0 5.8 (1–11) 4 4 7

LB (10) 10 0 0 5.3 (1–10) 7 3 6

Morphological

subtypes

Clinical stage

I IIa IIb IIIa IIIb IVa IVb

CP (20) 0 0 0 12 0 4 0

B (4) 0 0 0 0 0 0 4

SCC (5) 0 3 0 2 0 0 0

PM (10) 0 0 0 0 9 0 1

P (8) 0 0 0 1 0 0 1

LB (10) 0 0 0 0 0 0 3

CP, centroblastic polymorphic B lymphoma; B, Burkitt-type B lympho

lymphoma; P, plasmacytoid T lymphoma; LB, lymphoblastic T lymphoma;

megaly; gen, generalized; loc, localized; MM, mediastinal mass; BM, bone m

ND, not determined.

lastic polymorphic subtype was associated with a gen-

eralized lymphadenopathy which developed over 1–4

weeks (median, 2 weeks) without any other clinical

signs. Dogs were in clinical stages IIIa–Va. Two dogs

developed gastrointestinal signs (vomiting and diar-

rhoea) during the induction phase after the administra-

tion of cyclophosphamide, but they responded well toantiemetics and intestinal protectants (smectite, Smecta,

Ipsen). One dog became neutropenic during the induc-

tion cycle and had a dose reduction (10%) for

cyclophosphamide.

Concerning the Burkitt-type subtype, in addition to a

generalized lymphadenopathy, all dogs presented with

alimentary infiltration, assessed by cytological

l subtypes of canine lymphoma

MM Hepato-

megaly

Spleno-

megaly

Gut BM Hyper

calcaemiaLoc

0 0 3 7 0 4 0

0 0 4 4 4 ND 1

2 0 0 0 0 0 0

0 0 1 1 0 0 0

1 4 7 7 0 6 4

4 8 3 7 0 7 3

Va Vb

4 0

0 0

0 0

0 0

1 5

0 7

ma; SCC, small clear-cell T lymphoma; PM, pleomorphic mixed T

La, large; Med, medium; Sm, small; M, male; F, female; Ad, adeno-

arrow; and MFR and OST in months except written indication.

Table 5

Tumour response and survival data of the 57 cases according to morphological subtypes of canine lymphoma

Morphological subtypes Response FR median (range) OST median (range)

CP (20) CR 12 (9–18) 17 (14–24)

B (4) 1 PR, 3 SD 0 15 days (7–21)

SCC (5) CR 12 (6–24) 21 (12–26)

PM (10) CR 10 (6–14) 14 (9–16)

P (8) CR 2 (1–6) 3 (2–7)

LB (10) CR 8 (7–10) 9 (8.5–11)

CP, centroblastic polymorphic B lymphoma; B, Burkitt-type B lymphoma; SCC, small clear-cell T lymphoma; PM, pleomorphic mixed T

lymphoma; P, plasmacytoid T lymphoma; LB, lymphoblastic T lymphoma; FR and OST in months except written indication; CR, complete

response; PR, partial response; and SD, stable disease.

162 F. Ponce et al. / The Veterinary Journal 167 (2004) 158–166

examination, serious clinical signs such as anorexia,weakness and diarrhoea, and one had polyuria-poly-

dypsia with hypercalcaemia. Clinical signs developed in

less than one week. All the dogs were in clinical stage

IVb or maybe more; bone marrow aspirates were not

performed, due to the dogs� poor state of health. One

dog had a partial response to chemotherapy and the

three others remained stable. Death occurred with acute

gastrointestinal signs (haemorrhagic diarrhoea) in allcases.

Among the 33 T-cell NHL, five were small clear-cell,

10 were pleomorphic mixed, eight were unclassified

high-grade plasmacytoid, and 10 were lymphoblastic.

Among the five small clear-cell cases, three dogs pre-

sented a generalized superficial and two a localized

(mandibular and/or superficial cervical lymph nodes of

one side) lymphadenopathy that developed over severalmonths without any other clinical signs. Dogs were

classified as stages IIa–IIIa.

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

0 3 6 9 12

PR

OP

OR

TIO

N R

ES

PO

ND

ING

Fig. 1. Kaplan–Meier curve comparing FR duration in dogs with different mor

like subtype was considered to have no remission time, and is not reported in th

lymphoma; PM, pleomorphic mixed T lymphoma; CP, centroblastic polymo

All 10 cases of the pleomorphic mixed subtype pre-sented a generalized lymphadenopathy with various

clinical signs such as lethargy, weakness and weight loss,

developing over about 15 days. Dogs were classified as

stages IIIb–IVb.

For the eight cases of unclassified high-grade plas-

macytoid T-cell NHL, clinical signs developed within 1

week. The most significant clinical data were lymphad-

enopathy more often generalized (7/8 cases) and local-ized in one case (mediastinal and superficial cervical

lymph nodes), a mediastinal mass in four cases, bone

marrow involvement in six cases, and hypercalcaemia in

four cases, along with an aggressive clinical course and

severe systemic signs such as marked weakness and an-

orexia. Dogs were classified as stages III–V and mainly

as substage b.

In the 10 cases of lymphoblastic NHL, clinical signsdeveloped over 1–4 weeks. The main clinical data were

constant lymphadenopathy, either generalized (six

15 18 21 24 27

P (n=8)

LB (n=10)

PM (n=10)

CP (n=20)

SCC (n=5)

phological subtypes of canine NHL during chemotherapy. The Burkitt-

is figure. P, high-grade plasmacytoid T lymphoma; LB, lymphoblastic T

rphic B lymphoma; and SCC, small clear-cell T lymphoma.

Fig. 2. Kaplan–Meier curve comparing OST in dogs with different morphological subtypes of canine NHL during chemotherapy. B, Burkitt-type B

lymphoma; P, high-grade plasmacytoid T lymphoma; LB, lymphoblastic T lymphoma; PM, pleomorphic mixed T lymphoma; CP, centroblastic

polymorphic B lymphoma; and SCC, small clear-cell T lymphoma.

F. Ponce et al. / The Veterinary Journal 167 (2004) 158–166 163

cases) or localized (four cases with mandibular, super-

ficial cervical or mesenteric lymphadenopathy), a me-

diastinal mass in eight cases, bone marrow involvement

in seven cases, and hypercalcaemia in three cases. Seri-ous clinical signs such as weakness, anorexia, weight

loss, dyspnoea, and vomiting were noticed. Dogs were

classified as stages IVb–Vb.

The observed discrepancies between MFR or OST of

the different subtypes, based on the survival curves

(Figs. 1 and 2), were significant (p < 0:05).

4. Discussion

In human medicine, the oncologist�s common goal

has been to find a lymphoma classification that predictsoutcomes and responses to chemotherapy. Hence, in the

group of human NHL, there are a lot of distinct diseases

with their own prognostic relevance, associated with

distinctive responses to therapy, and for which unique

treatments are appropriate (Jaffe et al., 2001). For ex-

ample, gastric lymphomas often respond to the eradi-

cation of Helicobacter pylori, Burkitt�s lymphoma is

treated with a high dose treatment programme, whereasindolent lymphomas without pejorative prognostic fac-

tors are not treated until transformation to a high-grade

type (Solal-Celigny et al., 1997; Armitage, 1999; Isaac-

son, 2000; Jaffe et al., 2001).

In contrast, many canine lymphoma therapies have

been tested over the last 30 years without any distinction

between morphological subtypes (Greenlee et al., 1990;

Vail, 1993; Teske, 1994a,b; Teske et al., 1994a,b; Lucroy

et al., 1998; Zemann et al., 1998; Kiupel et al., 1999;

Madewell, 1999; Moore et al., 2001, 1999; Baskin et al.,2000; Boyce and Kitchell, 2000; Chun et al., 2000), ex-

cept for only one recent study on 49 cases of canine

lymphoma (Dobson et al., 2001). Nevertheless, in this

last study, the absence of low grade tumours, the low

percentage of T-cell lymphomas (13%), the questionable

grouping of the Burkitt, and the lymphoblastic subtypes

may be responsible for the lack of significant prognostic

differences between the identified morphological sub-types. In the present study, median OST was 14 months,

which is close to the majority of previously reported

veterinary data.

T-cell lymphomas, both in humans (Melnyk et al.,

1997; Solal-Celigny et al., 1997; Gisselbrecht et al., 1998;

Jaffe et al., 2001) and in dogs (Teske et al., 1994a,b;

Ruslander et al., 1997; Starrak et al., 1997; Kiupel et al.,

1999; Phillips et al., 2000; Dobson et al., 2001), are as-sociated with a poor prognosis. In our study, a com-

parison between the most frequently encountered canine

B and T-cell subtypes (i.e., the centroblastic polymor-

phic B-cell lymphoma and the pleomorphic mixed T-cell

lymphoma) showed that the MFR and OST were

significantly shorter for the latter. Consequently, com-

parisons between these most frequent subtypes con-

firmed that T-cell phenotype may be a prognostic factorassociated with a poor outcome. However, within each

group of B- and T-cell lymphomas, the various subtypes

164 F. Ponce et al. / The Veterinary Journal 167 (2004) 158–166

showed significant discrepancies and particularly theBurkitt-type B-cell subtype, with very short OST and

the small clear-T-cell subtype, with the longer MFR

and OST. In addition, the results of the present study

provide additional data, concerning clinical presenta-

tions and survival. They may contribute to the

characterization of clinico-morphological entities in

order to determine a canine lymphoma classification,

in the light of the new human REAL and WHOclassifications.

Among the B-cell lymphomas, the centroblastic

polymorphic lymphoma features may be compared with

those of canine lymphoma as a whole, as described in

the literature (Greenlee et al., 1990; Teske, 1994a,b;

Teske et al., 1994a,b; Madewell, 1999), given the fact

that centroblastic polymorphic lymphoma is the most

frequent subtype in all studies. In our series, however,both MFR and OST were longer than those previously

published for the entire spectrum of canine NHL

(Greenlee et al., 1990; Vail, 1993; Teske, 1994a,b; Teske

et al., 1994a,b; Lucroy et al., 1998; Zemann et al., 1998;

Kiupel et al., 1999; Madewell, 1999; Moore et al., 2001,

1999; Baskin et al., 2000; Boyce and Kitchell, 2000;

Chun et al., 2000). Within the B-cell category, the canine

Burkitt-type lymphoma is close to human equivalent,which is highly aggressive, often presenting at nodal

and/or extranodal sites, with a frequent gut involve-

ment, and 70% of patients presenting in advanced stages

(III and IV) (Grogan, 1999; Jaffe et al., 2001). In the

past, at the beginning of chemotherapy assays, relapse

occurred in less than one year. With a high dose treat-

ment programme, this disease is now potentially cur-

able. It argues for the necessity to look for newtherapeutic schemes for this VELCAP-unresponsive

subtype in dogs.

Among the T-cell lymphomas, the pleomorphic

mixed subtype may be compared to human peripheral

T-cell lymphomas, as defined by the REAL and WHO

classifications, with a lymph node enlargement, an ad-

vanced disease and a poorer outcome than that of dif-

fuse large B-cell lymphoma patients (Coiffier, 1999; Jaffeet al., 2001). Canine T-cell lymphoblastic lymphoma had

a slightly lower duration of MFR and of OST than

those of the pleomorphic mixed subtype. In humans,

lymphoblastic lymphoma is usually treated as a high-

risk disease, and prior to the advent of current thera-

peutic protocols, the prognosis was unfavourable

(Morel and Xerri, 1997; Knowles, 1999; Jaffe et al.,

2001) as in dogs at present time.Unclassified high-grade plasmacytoid T-cell lympho-

mas had a shorter MFR and OST than the other T-cell

subtypes. Until now, there is no clearly-established

human equivalent (Fournel-Fleury et al., 1997, 2002),

although it exhibits some similarities to sporadic cases

(Felman and Gentilhomme, 1997), which are classified

in the large group of ‘‘peripheral T-cell lymphomas

unspecified’’, and for which a unique therapeutic pro-tocol is used. This subtype thus raises the question of

being a particular entity, maybe requiring its own spe-

cific type of treatment.

Finally, the small clear-cell lymphoma has no definite

equivalent with any small T-cell lymphoma in humans,

but can be compared, in some respects, to the human T-

zone lymphoma (Lennert and Feller, 1991) which falls

into the group of unspecified peripheral T-cell lympho-mas. Its clinical behaviour seems to be similar to that of

the indolent human lymphomas, with survival measured

in years (Solal-Celigny et al., 1997; Harris, 1999; Jaffe

et al., 2001).

Each subtype seemed to be associated with a partic-

ular clinical presentation at the time of diagnosis, as in

humans. It could be that clinical stages might play a part

in these survival time discrepancies, especially for thesmall clear-cell subtype, where a longer OST could be

related to a low staging, and for the Burkitt-type sub-

type, where a shorter OST could be related to a high

staging. Therefore, clinical stages and mode of presen-

tation at diagnosis could, as in humans, be additional

criteria to distinguish the lymphomas with different re-

sponse rates (The International NHL Prognostic Fac-

tors Project, 1993; Solal-Celigny et al., 1997; Harris,1999; Jaffe et al., 2001).

Our study showed significant prognostic differences

between the clinico-morphological subtypes of canine

NHL. These observations are suggestive of inherent

biological features and clinical behaviour of these lym-

phoma entities. The subsumption of these subtypes into

one common category of NHL, or even two categories,

i.e., T- and B-cell lymphomas, would miss the prog-nostic heterogeneity within these groups and therefore

would fail to identify dogs which might require other

than the standard treatment.

Numerous studies have been undertaken to identify

prognostic factors relating to the response of lympho-

mas to treatment, and to the length of remission and

survival times. The factors investigated have included

age, gender, breed, weight, hypercalcaemia, clinicalstaging, and immunophenotype. The results of the

studies have been variable and conflicting (Greenlee

et al., 1990; Rosenberg et al., 1991; Teske, 1994b; Teske

et al., 1994a,b; Kiupel et al., 1999; Baskin et al., 2000;

Dobson et al., 2001; Jagielski et al., 2002). Therefore,

the next step should be to study these different prog-

nostic factors, and particularly clinical staging and

mode of presentation at diagnosis, within individualclinico-morphological entities, and not across the entire

spectrum of canine NHL, as in humans (International

NHL Prognostic Factors Project, 1993; Solal-Celigny et

al., 1997; Harris, 1999; Jaffe et al., 2001). Finally, dif-

ferent therapy protocols and new agents should be

tested, according to the specific disease entities of ca-

nine NHL.

F. Ponce et al. / The Veterinary Journal 167 (2004) 158–166 165

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