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Abstract
The biological significance of mast cells and angiogenesis in canine melanomas is unclear. Eighty canine
melanomas (56 malignant and 24 benign), investigated to determine the relationship between mast cell
count (MCC), microvessel density (MVD) and clinicopathology, revealed significantly higher MCC and
MVD counts in malignant melanomas. Evaluation of
the prognostic significance of MCC and MVD in malignant melanomas showed a significant correlation
between MCC and MVD both within and at the edges
of the tumour. Multivariate analysis indicated that
MCC and MVD were independent predictors of survival but the former was a significantly better prognostic marker. Greater numbers of mast cells and
microvessels were found in malignant melanomas of
poor prognosis. The findings demonstrate a prognostic
significance of MCC and MVD in canine melanocytic
tumours.
Received 12 July 2005; accepted 21 December 2005
Introduction
Melanocytic tumours account for 3% of all canine neoplasms and up to 7% of all malignant tumours.1 The most
frequently affected sites are the oral cavity (56%), lips
(23%), skin (11%) and digits (8%); other sites, including
the eyes, account for only 2%.2 Mast cells are prominent
in the tumour microenvironment and are thought to provide a host response to neoplasia.3 Increased numbers
have been noted in several human tumour types including
melanomas4 and breast carcinomas,5 but their functional
significance is unclear. Mast cells in tissues have been
implicated in angiogenesis and angiogenic factors, such
as heparin, tryptase, chymase, fibroblast growth factor
(FGF), vascular endothelial growth factor (VEGF) and
tumour necrosis factor (TNF), have been found in mast
cells.6 Angiogenesis is crucial for sustained tumour
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Follow-up study
Survival data for 18 of the dogs with cutaneous malignant melanomas
revealed no evidence of metastases to local lymph nodes or to distant
organs at the time of complete tumour removal. Neither chemotherapy nor radiotherapy was applied before or after surgical resection of
the tumour. Survival time was measured as the time from diagnosis
and resection to the time of death. The survival time was subdivided
into three periods: less than 12 months, 1224 months and more than
24 months.
Statistical analysis
The correlation between MCC and MVD was calculated using Spearmans correlation coefficient. Logistic regression analysis was used to
evaluate the relationship between malignancy and clinicopathological
features. The t-test was used to find the association between MCC
or MVD and tumour behaviour (benign or malignant), the association
between MCC, MVD and clinicopathological features and the association between MCC or MVD and prognostic subgroups. By using
cut-off values of media MCC and MVD, the dogs were divided into low
and high MCC and MVD groups. Overall survival rate was compared
between high and low MCC, and high and low MVD groups. Univariate
survival analyses were performed using the KaplanMeier method
and compared by the log-rank test. Multivariate survival analysis was
undertaken using Coxs proportional hazards model. A P-value < 0.05
was considered significant. The independent variables in the logistic
and Coxs models were MCC, MVD [at tumour edge and in whole
tumour (as continuous variable)], degree of invasion and degree of
pigmentation. The SPSS (SPSS for Windows, version 11.5, 1998) and
the S-PLUS (S-PLUS for Windows, version 6, 2001) computer programs
were used to analyse the data.
Results
Clinicopathology
Of the 80 canine melanoma cases, 42 (52.5%) were
males and 38 (47.5%) were females, and 56 (70%) of the
tumours were malignant. No significant relationship was
found between sex and tumour behaviour (benign or
malignant). Fifty-four percent of the melanomas were
from the skin, 24% from the oral cavity and 23% from the
ocular cavity. Oral melanomas were noted to be five times
more likely to be malignant than benign, whereas ocular
melanomas were observed to be twice as likely to be
benign (P < 0.01, OR = 5).
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2006 The Authors. Journal compilation 2006 European Society of Veterinary Dermatology.
Table 1. Summary of clinicopathological features of 80 canine melanomas and the association between mast cell count and microvessel density
at the invasive edge and in the whole tumour and various clinicopathological features
Parameter
Diagnosis
Benign melanoma
Malignant melanoma
Location
Cutaneous
Oral
Ocular
Histological type
Polygonal
Spindle
Mixed
Other types
Invasion
Noninvasive
Weak
Moderate
Strong
Pigmentation
Absent
Mild
Strong
Frequency (%)
24 (30%)
56 (70%)
1 0.2
12 9
< 0.01
4 0.7
34 11
< 0.01
16 5
39 5
< 0.01
43 (54%)
19 (24%)
18 (23%)
12 6
10 5
11 3
> 0.01
32 10
27 11
29 15
> 0.01
26 8
23 9
22 7
> 0.01
25 (31%)
28 (35%)
20 (25%)
7 (9%)
14 6
12 5
11 7
*NP
> 0.01
33 10
29 12
28 11
NP
> 0.01
27 7
23 6
26 7
NP
> 0.01
25 (33%)
3 (4%)
21 (26%)
31 (38%)
10 5
13 7
11 3
12 2
> 0.01
27 16
35 13
32 11
27 12
> 0.01
10 6
28 4
30 7
27 5
> 0.01
8 (10%)
43 (54%)
29 (36%)
14 5
13 3
12 4
> 0.01
29 15
33 18
37 12
> 0.01
18 7
29 3
32 7
> 0.01
Discussion
The results show that the location of the melanoma was
related to the biological behaviour of the tumour with oral
melanomas being associated more with malignancy
than cutaneous and ocular ones. This confirms the results
of Smith et al.21 The reason why oral melanomas tend
MCC
Whole tumour
Edges
MVD
Whole tumour
Edges
Good (n = 7)
Intermediate (n = 5)
Poor (n = 6)
5 0.05
18 0.5
8 1*
32 4*
15 4*
47 2*
18 4
28 7
27 6*
42 12*
39 6*
61 7*
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Figure 5. Overall survival for patients with low (< 18) and high (> 18)
microvessel density tumour edges by the KaplanMeier method
(P < 0.01).
Figure 4. Overall survival for patients with low (< 42) and high (> 42)
mast cell counts at tumour edges by the KaplanMeier method
(2 = 18.08, P < 0.01).
Variable
Significance
3.9 (1.834.91)
2.1 (1.823.09)
2.1 (1.952.80)
1.8 (1.102.97)
P < 0.01
P < 0.01
P < 0.01
P < 0.01
Acknowledgements
The authors thank Mr P. Mlambo and Mr J. Chigarisano for
technical assistance.
2006 The Authors. Journal compilation 2006 European Society of Veterinary Dermatology.
References
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Rsum La signification biologique des mastocytes et de langiognse dans les mlanomes canins nest
pas claire. Quatre-vingt mlanomes canins (56 malins et 24 bnins), ont t tudis pour dterminer la
relation entre les comptes de mastocytes (MCC), la densit de la microvasculature (MVD) et laspect
histologique. Des taux plus levs de MCC et MVD ont t observs dans les mlanomes malins. Lvaluation
de la signification pronostique de MCC et de MVD dans les mlanomes malins a montr une corrlation
significative entre MCC et MVD la fois dans et aux marges de la tumeur. Une analyse multivariance indiquait que MCC et MVD taient des lments pronostiques indpendants, mais le premier tait plus fiable.
Des taux plus importants de mastocytes et un nombre plus important de vaisseaux taient observs dans
les mlanomes malins de mauvais pronostic. Ces observations dmontrent une valeur pronostique de MCC
et MVD dans les tumeurs mlanocytaires du chien.
Resumen La importancia biolgica de los mastocitos y de la angiogenesis en melanomas caninos no est
bien determinada. Ochenta melanomas caninos (56 malignos y 24 benignos), que se investigaron para determinar la relacin entre el nmero de mastocitos, la densidad de la microvasculatura y los hallazgos clnicopatolgicos, revelaron un mayor numero de mastocitos y mayor densidad de microvasculatura en los
melanomas malignos. La evaluacin del significado pronstico del nmero de mastocitos y la densidad de
la microvasculatura en los melanomas malignos demostr una correlacin significativa entre el nmero de
mastocitos y densidad de microvasculatura tanto en el interior como en la periferia de los tumores. El anlisis
de multivarianza indic que el nmero de mastocitos y la densidad de la microvasculatura fueron factores
independientes predictivos de supervivencia, pero el nmero de mastocitos fue un mejor factor pronstico.
Un mayor nmero de mastocitos y una mayor densidad de microvasculatura se encontraron en los melanomas malignos con pronstico grave. Estos hallazgos demuestran la importancia pronstica del nmero de
mastocitos y de la densidad de microvasculatura en tumores melanocticos en perros.
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Zusammenfassung Die biologische Bedeutung von Mastzellen sowie die Angiogenese beim caninen
Melanom sind unklar. Achtzig canine Melanome (56 maligne und 24 benigne), die untersucht worden waren,
um den Zusammenhang von Mastzellzahl (MCC), Mikrogefdichte (MVD) und klinischer Pathologie zu
ermitteln, zeigten signifikant hhere MCC- und MVD-Werte in den malignen Melanomen. Die Evaluierung
der prognostischen Bedeutung der MCC- und MVD-Werte in malignen Melanomen zeigte eine signifikante
Korrelation zwischen MCC und MVD sowohl im Tumor, wie auch an den Rndern des Tumors. Multivariate
Analyse wies darauf hin, dass MCC und MVD voneinander unabhngige Faktoren darstellten bzgl. einer
Vorhersage des berlebens, allerdings war erstere ein signifikant besserer Marker zur Erstellung einer
Prognose. Die hchsten Zahlen an Mastzellen und Mikrogefen wurden bei malignen Melanomen mit
schlechter Prognose gefunden. Diese Ergebnisse veranschaulichen eine prognostische Bedeutung von
MCC und MVD bei caninen melanozytischen Tumoren.
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2006 The Authors. Journal compilation 2006 European Society of Veterinary Dermatology.