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Mast cells and angiogenesis in canine melanomas:

malignancy and clinicopathological factors


Blackwell Publishing Ltd

Sydney Mukaratirwa, Lynne Chikafa, Rachel


Dliwayo and Ndumiso Moyo
Department of Paraclinical Studies, Pathology Section, Faculty of
Veterinary Science, University of Zimbabwe, PO Box MP 167, Mount
Pleasant, Harare, Zimbabwe
Correspondence: S. Mukaratirwa, Department of Paraclinical Studies,
Pathology Section, Faculty of Veterinary Science, University of
Zimbabwe, PO Box MP 167, Mount Pleasant, Harare, Zimbabwe.
Fax: 263 4 333683;
E-mail: tmukaratirwa@vet.uz.ac.zw

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

growth as it allows oxygenation and nutrient perfusion


of the tumour and removal of waste products. Increased
angiogenesis coincides with increased tumour cell
entry into the circulation and thus facilitates metastasis.7
In humans, peritumoural accumulation of mast cells
favours tumour progression8 and mast cell density and
angiogenesis provide, in some instances, valuable prognostic
markers.6,9,10
Despite the rapid progression in understanding of the
biological and clinical significance of mast cells and angiogenesis in human cancers, there is little information on
their role in canine tumours. In veterinary oncology, studies
on the prognostic significance of angiogenesis have
been undertaken only on canine mast cell tumours11 and
canine1214 and feline15 mammary tumours. The objectives
of this study were to assess intratumoural and invasion
front mast cell counts (MCC) and microvessel density
(MVD) in canine melanomas and to analyse their clinicopathological role and prognostic significance.

Materials and methods


Case materials and histology
Records and histological material from 80 cases of canine melanomas
examined between 1986 and 2004 in the Section of Pathology, Faculty of Veterinary Science, University of Zimbabwe, were re-evaluated.
Age, sex, breed and location of the tumour were noted, and the
original diagnosis was confirmed from haematoxylin and eosin (H&E)
sections by routine microscopy. Tumours were classified according to
the World Health Organization classification of melanocytic tumours
of the skin of domestic animals.16 Cell types present and degrees of
invasion and pigmentation were recorded. Degree of invasion was
classified as noninvasive (tumour confined to the epidermis), weak
(tumour extending from epidermis into papillary dermis), moderate
(tumour infiltrating the reticular dermis) and strong (tumour infiltrating
the subcutaneous tissue). Degree of pigmentation was denoted
as absent, mild (< 40% of cells pigmented) or strong (> 40% of cells
pigmented).

Bleaching of melanin pigment


Melanin pigment was bleached from tissue sections before immunohistochemical labelling, as described by Roels et al.17 Briefly, sections
were incubated for 42 h at room temperature in 3% H2O2 in BSA (2%)
and disodium hydrogen phosphate (10 g L1).

Histochemical staining of mast cells


Mast cells were visualized by toluidine blue staining,18 and their densities within the tumour and also at the invasive edge were determined from 10 randomly selected fields (400) using an eyepiece
with a square-ruled grid with a total area of 0.2 mm2. The number of
mast cells per square millimeter was computed in each instance.

Immunohistochemical labelling of microvessels


A monoclonal antibody against the endothelial cell marker, factor VIII
(MAb M616, Dako, Glostrup, Denmark) was used to identify intratumoural microvessels. Deparaffinized bleached and unbleached

2006 The Authors. Journal compilation 2006 European Society of Veterinary Dermatology. 17; 141146

141

S Mukaratirwa et al.

sections of the tumours were stained using the avidinbiotin complex.


Negative controls were obtained by substituting the primary antibody
with nonimmune sera and a known positive control (haemangiosarcoma) was included. Endogenous peroxidase activity was blocked by
immersing the slides for 20 min in 3% H2O2 in methanol. The slides
were pre-incubated with 10% normal horse serum for 30 min before
incubation with the antibody MAb M616 (1:25 in Tris-buffered saline,
pH 7.6) overnight at 4 C. A biotinylated horse antimouse secondary
antisera and the avidinbiotinperoxidase were applied for 30 min.
Visualization was achieved by an enzymesubstrate reaction using
3,3-diaminobenzidine as a chromogen, and counterstaining with
Mayers haematoxylin. Microvessels (capillaries and small venules)
were counted, using a double-headed photomicroscope (Leitz Dialux
20, Leitz, Wetzlar, Germany) for simultaneous identification by two
individuals. Sections treated for microvessels were screened at
low power ( 100) to identify the areas of highest vascularization
(hot spots) within the whole tumour and at the tumour edges. Microvessel counts in the hot spots were performed at 400 magnification
using a square reticule (0.2 mm2). Any immunostained endothelial
cell or cell cluster clearly separate from adjacent vessels was
counted as a single microvessel, even in the absence of a vessel
lumen. MVD was expressed as number of microvessels per square
millimetre.8,19,20

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).
142

The most common histological tumour cell type was


the spindle cell (35%), followed by the polygonal (31%)
and the mixed (25%) (Table 1). Other histological types,
including clear cell, adenomatous and papillary types were
uncommon (Table 1). Polygonal cell type melanomas were
found to be five times more malignant than the mixed
type melanomas (P < 0.01, OR = 5), and the mixed cell
type melanomas were 2.5 times more malignant than the
spindle cell type (P < 0.01, OR = 2.5). The percentage of
tumours in different groups of invasion is shown in
Table 1. Polygonal cell type melanomas were found to
be three times more invasive than the mixed type
melanomas (P < 0.01, OR = 3), and the mixed cell type
melanomas were twice more invasive than the spindle
cell type (P < 0.01, OR = 2). Ninety percent of the melanomas were pigmented, and there was no relation between
pigmentation and tumour behaviour (benign or malignant)
or degree of invasiveness.
Relationship of clinical outcome to MCC or MVD
In toluidine blue-stained sections, mast cells appeared
purple due to the presence of the metachromatic granules
(Fig. 1). Factor VIII positive endothelial cells were labelled
brown (Fig. 2). MCC and MVD at the tumour edges were
significantly higher than those in the whole tumour (P <
0.01), and there was a significant correlation between
MCC and MVD both at tumour edges (r = 0.94; P < 0.01)
(Fig. 3) and within them (r = 0.91; P < 0.01).
Malignant melanomas had a significantly higher
(P < 0.01) MCC and MVD at both the tumour edges and
within the whole tumour than benign melanomas
(Table 1). There was no significant correlation between
MCC or MVD and other clinicopathological factors (location of the tumour, degree of invasion and pigmentation)
(Table 1).
Survival analysis
Of the 18 dogs with survival data, five died within
6 months of diagnosis, five between 12 and 24 months
(intermediate prognosis) and seven after 2 years because
of tumour recurrence and metastases (confirmed on
necropsy).
The dogs were therefore divided into three prognostic
subgroups; those alive 24 months after tumour resection
(good prognosis, n = 7), dogs which died from tumour
recurrence between 12 and 24 months after resection
(intermediate prognosis, n = 5) and dogs which died from
tumour recurrence before 12 months (poor prognosis,
n = 6) (Table 2). There were significant MCC and MCD
differences between the three subgroups (at both the
tumour edges and in the whole tumour) (Table 2). The
MCC and MVD were significantly higher in the intermediate over the good prognosis subgroup (P < 0.01), and also
significantly higher in the poor subgroup over intermediate
subgroup (P < 0.01) and hence the good subgroup.
Using cut-off values of median MCC (42 at tumour
edges, 12 in the whole tumour) and MVD (18 at tumour
edges, 13 in the whole tumour), the dogs were divided
into low and high MCC or MVD groups. Survival rate was
compared between the high MCC and low MCC groups,
and between the high MVD and low MCD groups. Dogs
in the high MCC group at both the tumour edges and in the

2006 The Authors. Journal compilation 2006 European Society of Veterinary Dermatology.

Angiogenesis in canine melanomas

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 (%)

Mean MCC (whole)

Mean MCC (edge)

Mean MVD (edge)

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

*NP, not performed.

Figure 1. Section from within a canine malignant melanoma stained


for mast cells (mc, purple). m, melanin (brown); n, nucleus of
melanoma cells. Toluidine blue. 400.

tumour had a significantly worse prognosis than those in


low group (P < 0.01; Fig. 4). Dogs in the high MVD count
group at both the tumour edges and in the whole tumour
similarly had a significantly worse prognosis (P < 0.01;
Fig. 5). MCC was significantly a better prognostic marker
than MVD (P < 0.01).
Both MCC and MVD at the tumour edges and in the
tumour were independent prognostic factors (Table 3).
Degrees of invasion and of pigmentation were not
prognostic factors.

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

Figure 2. Section from within a canine malignant melanoma processed


for factor VIII. mv, microvessels with labelled endothelial cells (brown);
n, nuclei of melanomas cells. Avidinbiotin peroxidase complex, H&E
counterstain. 400.
Table 2. Mast cell count and microvessel density in 18 canine
malignant melanomas: relation with prognosis
Prognostic subgroup

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*

*P < 0.01 compared with the preceding group ( 2 test).

to be malignant and more aggressive than cutaneous


and ocular ones is unclear. In humans, high-risk sites for
metastasis in primary malignant melanomas have a rich
vascular supply,22 and this has led to speculation that

2006 The Authors. Journal compilation 2006 European Society of Veterinary Dermatology.

143

S Mukaratirwa et al.

Figure 3. Correlation between mast cell count and microvessel


density at tumour edge (r = 0.94; P < 0.01).

Figure 5. Overall survival for patients with low (< 18) and high (> 18)
microvessel density tumour edges by the KaplanMeier method
(P < 0.01).

Table 3. The independent prognostic factors in Coxs multivariate


survival analysis

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).

sites with high vascularization provide a readily accessible


vascular pathway for the dissemination of malignant cells.
Because the oral cavity is well vascularized and has a good
lymphatic vessel network, it provides an ideal environment for tumour proliferation and growth and enhances
the chances of tumour metastasis, hence its association
with malignant melanomas.
Tumour invasion and metastasis result from aberrant
communication between tumour cells and its microenvironment. The skin microenvironment consists of a variety
of host stromal cells: vascular cells, inflammatory cells,
fibroblasts and myofibroblasts. The positive correlation
between MCC and MVD observed in this study suggest
that mast cells are important for the neovascularization
of canine melanocytic tumours. Tumours in mast celldeficient mice have reduced vascularity and produce
fewer metastases.23 However, accumulation of mast cells
has also been observed in experimentally induced tumours
before the onset of tumour-associated angiogenesis.24
The high number of mast cells and blood vessels in
malignant tumours, especially at the margins, suggests
that mast cells and angiogenesis are crucial for the progression of canine melanomas. Mast cells probably promote
angiogenesis in these tumours. Angiogenic factors produced by mast cells directly affect endothelial cells by
144

Variable

Relative risk (95% CI)

Significance

MCC tumour edge


MCC of tumour
MVD tumour edge
MVD of tumour

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

stimulating their migration and proliferation, or indirectly


affect endothelial cells by degrading the connective tissue
matrix, thereby providing space for formation of neovascular sprouts.25 As MCC and MVD were significantly
higher at the tumour edges than in the tumour, it seems
that tumour cells at the invasion front are more capable of
inducing mast cell migration. Although the mechanisms of
how mast cells accumulate in tumours or at tumour edges
are not clear, Ribatti et al.26 suggested that hypoxia within
the tumour induces mast cell migration into the hypoxic
regions and production of angiogenic factors that promote
infiltration of more mast cells.
Mast cell counts and MVD have been reported as
possible prognostic indicators in numerous human solid
tumours including melanomas,19 squamous cell carcinomas
of the oesophagus9 and lung adenocarcinomas.7 In this
preliminary study, using a limited number of cases, high
MCC and MVD in canine skin were also associated with a
poor prognosis. More detailed study with many cases is
required to confirm these results.
In conclusion, the findings accord with the situation in
several human tumours where there is a close relationship
between MCD and angiogenesis during tumour progression and indicate a prognostic role for MCC and MVD in
canine melanomas.

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.

Angiogenesis in canine melanomas

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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.

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