Veterinary Surgery

37:466–471, 2008

Histologic Prognosticators in Feline Osteosarcoma: A Comparison

with Phenotypically Similar Canine Osteosarcoma

MARIA DIMOPOULOU, DVM, JOLLE KIRPENSTEIJN, Prof, DVM, PhD, Diplomate ACVS & ECVS, HESTER MOENS, DVM,
and MARJA KIK, DVM, PhD

Objective—To investigate the histologic characteristics of feline osteosarcoma (OS) and compare
the histologic data with phenotypically comparable canine OS. The effects of histologic and clinical
variables on survival statistics were evaluated.
Study Design—Retrospective study.
Animals—Cats (n ¼ 62) and dogs (22).
Methods—Medical records of 62 cats with OS were reviewed for clinically relevant data. Clinical
outcome was obtained by telephone interview. Histologic characteristics of OS were classified using
a standardized grading system. Histologic characteristics in 22 feline skeletal OS were compared
with 22 canine skeletal OS of identical location and subtype. Prognostic variables for clinical
outcome were determined using multivariate analysis.
Results—Feline OS was characterized by moderate to abundant cellular pleomorphism, low mitotic
index, small to moderate amounts of matrix, high cellularity, and a moderate amount of necrosis.
There was no significant difference between histologic variables in feline and canine OS. Histologic
grade, surgery, and mitotic index significantly influenced clinical outcome as determined by multi-
variate analysis. Tumor invasion into vessels was not identified as a significant prognosticator.
Conclusion—Feline and canine skeletal OS have similar histologic but different prognostic char-
acteristics.
Clinical Relevance—Prognosis for cats with OS is related to histologic grade and mitotic index of
the tumor.
r Copyright 2008 by The American College of Veterinary Surgeons

INTRODUCTION Feline OS can be located in appendicular, axial,

and extraskeletal sites. Occurrence of skeletal OS in

O STEOSARCOMA (OS) is the most common bone

tumor in the cat, accounting for 70–80% of all pri-
mary bone tumors.1,2 Feline bone tumors are uncommon,
with a reported incidence of 3.1–4.9 per 100,000 cases and
an average age of occurrence of 8–10 years.3,4 OS are
generally defined as tumors composed of malignant
mesenchymal spindle cells that produce an extracellular
matrix of bone or osteoid.
appendicular and axial sites seems evenly distri-
buted,5–7 and extraskeletal OS (EOS) account for up to
40% of all feline OS.6 Subcutaneous EOS is most com-
mon, with sporadic reports of occurrence in the
mammary gland, the eye, and other locations.6,8–18 Feline
EOS have been linked to injection sites6,12,13,19 and
seem to carry a poorer prognosis than skeletal
OS.6,10,16,17,20

From the Department of Small Animal Clinical Sciences, Faculty of Life Sciences, University of Copenhagen, Copenhagen, Denmark;
and the Departments of Clinical Sciences of Companion Animals, and Pathobiology, Faculty of Veterinary Medicine, Utrecht University,
Utrecht, The Netherlands.
This study was performed at the Departments of Clinical Sciences of Companion Animals, and Pathobiology, Faculty of Veterinary
Medicine, Utrecht University, Utrecht, The Netherlands.
Address reprint requests to Prof. Dr. J. Kirpensteijn, Department of Clinical Sciences of Companion Animals, Faculty of Veterinary
Medicine, Utrecht University, PO Box 80154, 3508 TD Utrecht, The Netherlands. E-mail: j.kirpensteijn@uu.nl.
Submitted July 2007; Accepted October 2007
r Copyright 2008 by The American College of Veterinary Surgeons

0161-3499/08
doi:10.1111/j.1532-950X.2008.00409.x
466
 DIMOPOULOU ET AL
Feline OS behave differently compared with canine
OS. Whereas an incidence of metastasis of up to 80–90%
is described for dogs,21–25 only 5–10% of feline OS are
reported to metastasize.5,6,26 Because of this low meta-
static rate, the therapy of choice has been wide surgical
excision of the tumor. Feline appendicular OS is often
amenable for wide surgical excision and showed longer
survival rates compared with feline axial and EOS.1,5,6
Isolated case reports of feline OS treated with adjunctive
chemotherapy and radiotherapy promise longer survival
times (ST).6,8,15
Histologic evaluation of feline OS may identify vari-
ables that differ between the cat and the dog and between
different tumor types. These variables may influence
prognosis and clinical outcome after surgical manage-
ment. Although OS have previously been divided into
morphologic subtypes such as osteoblastic, fibroblastic,
chondroblastic, teleangiectatic, and mixed types, sig-
nificant correlation between the subtypes and survival
statistics in humans27–29 and dogs is lacking.22,30 In con-
trast to subtyping, histologic grading is an effective prog-
nostic factor in human29 and canine OS.22 No data are
available in the current literature of using a histologic
classification or grading system in the cat.
Our purpose was to histologically assess and stan-
dardize feline OS, to compare histologic variables among
appendicular, axial, and EOS and to pair feline to canine
skeletal OS data of identical location and histologic sub-
type. The prognostic significance of histologic grading on
the clinical outcome of feline OS was evaluated.
MATERIALS AND METHODS
Animals
Cats. Medical records of 62 cats (1994–2004) with OS
diagnosed by histologic examination were studied. Recorded
data were breed, sex, age (years), tumor location, and therapy
protocol.
Dogs. Twenty-two dogs with skeletal tumors of identical
location and subtype corresponding to 22 feline skeletal OS
were included in the study. Dogs were selected from among a
group of dogs with histologically confirmed OS admitted to
our hospital from 1985 to 1999.
Biopsy Specimens
Tumor tissue samples were collected at surgery or at nec-
ropsy immediately after euthanasia. Biopsy specimens were
obtained using a Michele trephine or by incision of the tumor.
Specimens were fixed in neutral buffered 10% formalin and
processed for histology and stained with hematoxylin and
eosin stain.
467
Histologic Analysis
All slides were blindly evaluated using a standardized
histologic grading system by a certified pathologist (M.K.).
Tumors characterized by mesenchymal spindle cells producing
osteoid were defined as OS. Histologic variables included
matrix type, tumor invasion into blood vessels, tumor cell
pleomorphism (TCP), number of mitoses, percentage tumor
matrix, tumor cell density, amount of necrosis, number of
multinucleated giant cells (MNGC), and whirl formation.
Histologic subtypes were defined as osteoblastic, chondro-
blastic, fibroblastic, teleangiectatic, and mixed.
All variables were scored subjectively using a predeter-
mined classification system, adapted from a reported veteri-
nary system (Table 1).22 Invasion of tumor in the vessels was
evaluated throughout the entire biopsy specimen (0 ¼ no signs
of tumor growth into the vessels, 3 ¼ tumor invasion into
blood vessels). TCP was evaluated on a scale of 1–3
(1 ¼ o25% TCP, 2 ¼ 25–50% TCP, 3 ¼ 450% TCP). Num-
ber of mitoses was calculated by adding the number of cells in
mitosis of 3 randomly selected high-power fields (
400) and
evaluated on a scale of 0–3 (0 ¼ no mitosis, 2 ¼ 1 mitosis,
3 ¼ 41 mitosis). The amount of tumor matrix was evaluated
on a scale of 1–3 (1 ¼ 450% tumor matrix, 2 ¼ 25–50% tu-
mor matrix, 3 ¼ o25% tumor matrix). Tumor cell density was
evaluated on a scale of 1–3 (1 ¼ o25% tumor cells, 2 ¼ 25–
50% tumor cells, 3 ¼ 450% tumor cells). Tumor necrosis was
evaluated on a scale of 1–3 (1 ¼ o25% necrosis, 2 ¼ 25–50%
necrosis, 3 ¼ 450% necrosis). Number of MNGC was esti-
mated on a scale of 0–3 (0 ¼ no MNGC, 1 ¼ minimal number
of MNGC, 2 ¼ moderate amount of MNGC, 3 ¼ large num-
ber of MNGC). Whirl formation was estimated on a scale of
0–3 (0 ¼ no whirl formation, 1 ¼ minimal whirl formation,
2 ¼ moderate whirl formation, 3 ¼ maximal whirl formation).
Tumor grade for each animal was calculated by adding the
individual scores of each histologic variable (Table 1).
Follow-Up
Either the owner of the cat or the referring veterinarian was
contacted by telephone, and a standard questionnaire was
performed, including questions concerning breed, sex, age,
disease-free interval (DFI), metastasis occurrence, tumor
recurrence, ST, and cause of death.
Statistical Methods
Frequency distributions were calculated and categorical
data were compared using w2 analysis, where necessary.
A Fisher’s exact test was performed if 425% of cells had
expected counts o5. Normally distributed, continuous and
interval categorical data were analyzed using an analysis
of variance (ANOVA). Logarithmic transformation was
performed on variables that were not normally distributed.
A hazard ratio (HR) of different variables on DFI, recurrence-
free interval (RFI), and ST was calculated using multivariate
Cox proportional hazards analysis. Po.05 was considered
significant.
468 HISTOLOGIC GRADING OF FELINE OSTEOSARCOMA

Table 1. Classification Schedule for Determination of Tumor Grade Table 3. Comparison of Mean ( SD) Scores of Histologic Variables of
Appendicular, Axial, and Extraskeletal Feline OS
Tumor
Cells Tumor Tumor Histologic Variables Appendicular Axial Extraskeletal
in Vessels Pleomorphism Mitoses Matrix Cells Necrosis
Pleomorphism 2.32  0.67 2.29  0.64 2.32  0.71
0 (No) 1 (o25%) 0 (0) 1 (450%) 1 (o25%) 1 (o25%) Number of mitoses 2.89  4.54 3.62  6.36 3.14  2.43
2 (25–50%) 2 (1) 2 (25–50%) 2 (25–50%) 2 (25–50%) Amount of tumor matrix 3.11  0.31 3.29  0.64 3.32  0.57
3 (Yes) 3 (450%) 3 (41) 3 (o25%) 3 (450%) 3 (450%) Tumor cell density 1.95  0.70 2.10  0.53 1.95  0.84
Amount of necrosis 1.79  0.92 1.43  0.75 1.91  0.87
Amount of multinucleated 1.37  0.89 1.76  0.89 1.27  0.88
giant cells
RESULTS Whirl formation 1.16  1.0 1.19  0.98 1.50  0.96

Cats

Four different breeds were represented including 59

European Shorthair cats (93.5%), 1 Siamese, 1 Persian,
and 1 mixed breed. The mean age was 10.7 years (range,
1–17.2 years). There were 37 castrated male, 21 spayed,
and 4 intact female cats, with a male-to-female ratio of
1.48.
Localization (Table 2)
There was an even distribution between left-sided
(n ¼ 24) and right-sided tumors (23). Osseous (40) were
more common than EOS (22) tumors. The maxilla, man-
dible, digits, scapula, proximal humerus, and tibia were
the most frequently affected skeletal sites. Most EOS oc-
curred in the interscapular area, flank region, and mam-
mary glands.
in any histologic variables were observed among extra-
skeletal, axial, and appendicular OS (Table 3). The most
common feline OS subtypes were osteoblastic and mixed
osteoblastic/fibroblastic (Table 4).
Significantly less whirl formation in the osteoblastic
subtype was present compared with the other feline sub-
types (P ¼ .036), whereas the other histologic variables
were not significantly different (Table 5). Histologic tu-
mor grade was neither significantly different between OS
subtypes nor location.
Tumor grade and histologic variables of feline skeletal
OS showed no significant differences compared with the
corresponding canine skeletal OS, although the number
of mitoses in feline OS (4.86  6.96) was almost half the
number of mitoses in canine OS (8.45  7.96; Table 6).

Histologic Analysis Outcome

Summarily, feline OS had moderate to abundant Sixty-two cats were used for statistical analysis of the
pleomorphism, had a low mitotic index, produced small histologic variables. Of the 62 cats, 2 were euthanatized
to moderate amounts of tumor matrix, but were relatively on admission, 43 had surgical excision of the tumor, and
cellular. Most tumors had a moderate amount of necro- 17 had a biopsy. At follow-up, 36 cats had died (1 during
sis, a moderate amount of MNGC, and little whirl surgery), 12 were alive, and 12 were lost to follow-up. Of
formation. Almost all OS (82.3%) had signs of tumor cell 48 cats with sufficient follow-up, 24 (50%) had died from
invasion within blood vessels. No significant differences a disease-related cause: 19 had local recurrence, 4 had
distant metastases, and 1 had local recurrence and distant
Table 2. Localization of Feline OS
metastases. One cat was alive with a recurrence and the
2 cats euthanatized directly after diagnosis did not have
Extraskeletal Frequency Appendicular Frequency Axial Frequency
metastases. In all, recurrence frequency was 44% and
Interscapular 5 Digit 4 Maxilla 7
Mammary 4 Proximal 3 Mandible 4
glands humerus Table 4. Frequency of Feline OS Subtypes
Flank 4 Proximal tibia 3 Scapula 4 Subtype Frequency Percent
Neck 2 Proximal femur 2 Skull 3
Head 2 Proximal radius 1 Rib 2 Osteoblastic 26 41.9
Spleen 1 Metacarpus 1 Vertebra 1 Fibroblastic 5 8.1
Kidney 1 Metatarsus 1 Pelvis 1 Mixed osteoblastic/chondroblastic 3 4.8
Hind leg 1 Nasal cavity 1 Mixed osteoblastic/fibroblastic 19 30.6
Stomach 1 Tail 1 Mixed osteoblastic/teleangectatic 5 8.1
Axilla 1 Zygomatic 1 Mixed osteoblastic/chondroblastic/ 4 6.5
arch fibroblastic
Total 22 Total 15 Total 25 Total 62 100.0
 DIMOPOULOU ET AL 469

Table 5. Comparison of Mean ( SD) Scores of Histologic Variables of prognosis in both canine and feline OS. Canine OS
Osteoblastic Versus Other Feline OS Subtypes metastasizes primarily hematogenously30 and tumor
Variables Osteoblastic Other Subtypes invasion into vessels has been reported in  70% of tu-
mors.22,24 Most feline OS (82%) had tumor invasion into
Pleomorphism 2.19  0.63 2.39  0.72
Number of mitoses 3.04  5.53 3.52  4.28 blood vessels, a feature that in canine OS has been as-
Amount of tumor matrix 1.85  0.83 1.74  0.63 sociated with a high-grade tumor and poor prognosis.22
Amount of necrosis 1.58  0.81 1.81  0.91 This histologic feature, however, was not identified as a
Amount of multinucleated 1.46  0.91 1.48  0.89 prognostic indicator for feline OS.
giant cells
Histologic grading system was found to be a signifi-
Whirl formation 0.88  0.77 1.39  0.96
cant prognostic indicator for ST, DFI, and RFI in feline
Po.05. OS. To our knowledge, this is the first reported histologic
system to be used for classifying feline OS. Histologic
metastatic frequency was 10%. All local recurrences were tumor grade, assessing biologic aggressiveness, is being
confirmed by histologic or cytologic analysis. increasingly used as an aid to prognosis and therapy in
oncologic patients. Histologic grade has been identified as
Survival Analysis a prognostic factor in both human29,31 and canine OS.22
The prognostic value of tumor grading has also been
For 43 cats that had tumoral excision, increased HR demonstrated in other tumor types of mesenchymal
for shorter ST were observed for incomplete surgical re- origin, such as hemangiosarcoma,32 splenic,33 synovial
section (HR ¼ 2.63, 95% confidence interval [CI]: 1.1–6.3; cell,34 soft tissue sarcoma,35 and feline fibrosarcoma.36,37
P ¼ .03) and for increased histologic tumor grade Tumor grading can easily be used clinically as an aid in
(HR ¼ 1.48, 95% CI: 1.1–2.1, P ¼ .021). Cats with determining prognosis for the feline OS patient and the
incomplete surgical resection of the tumor (HR ¼ 3.15, decision making for use of adjunctive therapies.
95% CI: 1.4–7.1, P ¼ .006) and with higher histologic The only specific histologic variable that significantly
tumor grade (HR ¼ 1.46, 95% CI: 1.1–1.9, P ¼ .006) also affected survival statistics was mitotic index. The number
had increased hazard for shorter DFI. For RFI, in- of mitoses has been previously used in histologic grading
creased HR were observed for incomplete surgical systems, and its impact on tumor recurrence, metastasis,
resection (HR ¼ 3.71, 95% CI: 1.4–10.0, P ¼ .01) and in- and ST has been reported. Increased number of mitoses
creased tumor grade (HR ¼ 1.54, 95% CI: 1.1–2.1, has been identified as a significant hazard for poor prog-
P ¼ .009). Among the histologic variables used for pre- nosis in canine OS,22 feline fibrosarcoma,38 the diffuse
dicting the tumor grade, tumors with high number of form of feline cutaneous mast cell tumor,39 and soft tissue
mitosis had increased hazard for shorter RFI (HR ¼ 1.24, sarcoma.40 In our study, increasing number of mitoses
95% CI: 1.0–1.5, P ¼ .037). was a significant hazard for shorter RFI. This supports
the use of presurgical biopsy to guide the extent of sur-
DISCUSSION gical excision to minimize the recurrence risk.
Clinical findings for feline OS in our study were similar
The histologic characteristics of feline skeletal OS were to previous reports.1,2,5–7 Although OS is generally a tu-
not significantly different from corresponding canine mor of the older cat and mean age of diagnosis was 10.7
skeletal OS. Although not statistically significant, the years, there is a wide range of distribution, and therefore,
number of mitoses observed in feline OS was lower than OS cannot completely be ruled out in the young cat. In
in canine OS. This difference may be of interest, because accord with earlier reports, we found no sex or breed
a high mitotic index was significantly associated with a predisposition.5–7 Mean metastatic rate was 10%, and
more aggressive tumor behavior and a less favorable 44% of feline OS had local recurrence. Recurrence fre-
quency was influenced by marginal excision and the high
Table 6. Comparison of Mean ( SD) Scores of Histologic Variables of number of axial and EOS. Distribution between extra-
Feline and Canine OS skeletal (35%) and skeletal OS (65%) was similar to an-
Variable Feline Canine other retrospective study.6
Among the clinical variables that were evaluated as
Pleomorphism 2.41  0.67 2.68  0.72
Number of mitoses 4.86  6.96 8.45  7.96
prognostic indicators using multivariate analysis, only
Amount of tumor matrix 1.73  0.83 1.86  0.56 complete surgical resection had a significant effect on ST,
Percentage tumor cells versus matrix 2.00  0.76 2.00  0.31 DFI, and RFI. This factor was also prognostic in similar
Amount of necrosis 1.50  0.86 1.91  0.68 studies of canine OS22 and of soft tissue sarcomas.40
Amount of multinucleated giant cells 1.59  0.96 1.14  0.94 Although the recurrence rate in feline OS appears to be
Whirl formation 1.14  1.13 0.95  1.12
high (44%) according to our study, cats that had surgery
470 HISTOLOGIC GRADING OF FELINE OSTEOSARCOMA
had increased ST and time to recurrence compared with
animals that had no resection at all. It is possible that
surgery in combination with adjunctive chemotherapy can
further prolong ST and recurrence-free periods for feline
OS. Although some case reports of feline OS treated with
surgery and adjunctive chemotherapy have shown long
ST and recurrence-free periods,6,8,15 there are currently
no blinded studies that evaluate the role of chemotherapy
and radiation in the management of feline OS.
We conclude that feline OS has variation in histologic
appearance that is not related to tumor localization.
Histologic characteristics of feline OS are similar to those
observed in canine skeletal OS. Histologic grade and mi-
totic index seem to be the most important prognostic
factors for survival.
ACKNOWLEDGMENTS
The authors thank James Miles for critically reviewing the
article. This study was partly funded by a gracious
donation from The IAMS Company (Procter & Gamble).
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