Download Four-Fraction Radiation Therapy for Macroscopic Soft Tissue

Four-Fraction Radiation Therapy for
Macroscopic Soft Tissue
Sarcomas in 16 Dogs
A retrospective study of 16 dogs with macroscopic soft tissue sarcomas was performed to
evaluate response to a four-fraction radiotherapy protocol (prescribed dose of 32 Gy).
Radiation was well tolerated with minimal side effects. The overall response rate was 50%,
with seven partial responses and one complete response. The median time to progression
was 155 days, and the median survival time was 309 days. Coarsely fractionated radiation
therapy may be a reasonable palliative option for dogs with unresectable soft tissue sarcomas, although the response is relatively short-lived. J Am Anim Hosp Assoc 2008;44:100-108.
Jessica Lawrence, DVM,
Diplomate ACVR
(Radiation Oncology)
Lisa Forrest, VMD,
Diplomate ACVR (Radiology,
Radiation Oncology)
William Adams, DVM,
Diplomate ACVR (Radiology,
Radiation Oncology)
David Vail, DVM,
Diplomate ACVIM (Oncology)
Douglas Thamm, VMD,
Diplomate ACVIM (Oncology)
RS
From the Departments of Surgical
Sciences (Lawrence, Forrest, Adams)
and Medical Sciences (Vail, Thamm),
School of Veterinary Medicine,
University of Wisconsin-Madison,
2015 Linden Drive,
Madison, Wisconsin 53706.
Doctor Thamm’s current
address is Animal Cancer Center,
Colorado State University,
300 West Drake Road,
Fort Collins, Colorado 80523.
100
Palliative (i.e., coarsely fractionated) radiation therapy (RT) has been
used for provisional pain relief and improvement of dysfunction in both
people and animals suffering from primary or metastatic neoplasia.1,2
The use of coarsely fractionated RT in veterinary medicine has principally been tailored toward management of canine osteosarcoma and
melanoma, but some interest has been shown in similar protocols for
temporary control of various advanced malignancies and their associated
pain.1 “Definitive” RT remains the ideal approach for those animals in
which long-term control may be achieved, while palliative therapy is usually reserved for dogs in which curative measures are not feasible.3-5
The radiation dose and fractionation scheme often depend on the reason for the therapy, the general health status of the dog, the volume of tissue to be treated, the relative sensitivity of the tumor type, and the critical
organs or tissue that may be included in the treatment field.6 Toxicity is
directly related to the tissue irradiated and increases with the overall volume of irradiated tissue, the overall delivered dose, and the dose per fraction.6 Acute side effects primarily depend on the overall radiation dose,
the duration of the protocol, and the fraction size.5-7 Late radiation side
effects depend particularly on fraction size and less so on overall duration.5-7 Large fraction sizes of radiation are particularly damaging to
slowly dividing or nondividing normal tissue, such as connective tissue,
nervous tissue, muscle, and bone.5-7 Toxicity to these late-responding tissues typically shows up >3 to 6 months after radiation, and it is dose
dependent. This radiation damage is irreversible, progressive, and permanent, because the connective tissue structure and normal vasculature
are compromised.6,7,9
Curative radiation protocols generally consist of relatively low doses
per fraction (1.8 to 3.0 Gy) delivered daily for many weeks.6 However, it
is difficult to lower the dose per fraction to ≤2.0 Gy in veterinary medicine because of the prolonged treatment time required to reach a tumoricidal dose.8 Such long treatment regimens would require excessive
anesthesia (i.e., dogs are anesthetized for each fraction of radiation) and
hospitalization. This has led to a compromise in which dogs are treated
with a regimen with slightly higher doses per fraction.
Introduction
JOURNAL of the American Animal Hospital Association
May/June 2008, Vol. 44
Coarsely fractionated or “palliative” RT is typically
reserved for controlling the discomfort, localized hemorrhage, and tumor progression associated with incurable cancer.2,10 Typical protocols involve large radiation doses (5 to
10 Gy) delivered as a few fractions once or twice weekly.
Examples of coarse-fractionated protocols include (but are
not limited to) four fractions of 8 Gy each delivered once
per week, five fractions of 4 Gy given daily or once per
week, and one fraction of 10 Gy or six fractions of 5 to 6 Gy
delivered at a rate of one fraction per week.
Many incurable tumors are sizeable, requiring treatment
of a large radiation field. Administration of higher dose
fractions to a large volume of tissue increases the risk of late
radiation side effects.5,10,11 Lower doses per fraction are
preferred for palliative therapy, so as to preserve normal tissue structure and function.5,8 Unfortunately, some veterinary facilities have access to a radiation treatment center for
only 1 to 2 days per week. Delivery of a small fraction size
once per week is unlikely to lead to a durable response,
because tumor cells have a significant amount of time to
repair damage and to proliferate between treatments.5,8
Therefore, large doses of radiation are often delivered to
optimize killing of tumor cells, with the increased risk of
late radiation toxicity accepted as a part of treatment.27
Concern for clinically significant late effects can be
addressed by delivering lower doses of radiation, such as 4
Gy given daily in five fractions. However, most dogs
receive palliative therapy to improve quality of life, not to
prolong life, and they may not live long enough to experience permanent effects.
A protocol using larger dose fractions also decreases the
frequency of anesthesia. Dogs with advanced heart disease,
renal insufficiency, or widespread metastasis may benefit
from a course of RT that minimizes the frequency of general anesthesia, particularly if the tumor is causing only localized discomfort.2,27 Coarsely fractionated RT may offer
short-term relief without compromising life expectancy,
which is generally reduced by systemic disease, regardless
of the treatment chosen for the cancer.2,10,27
Soft tissue sarcomas represent a histologically diverse
group of mesenchymal tumors that tend to behave similarly.10 Typical locations include the skin and subcutaneous
tissues, although sarcomas can arise from any mesenchymal
tissue in the body.10 These tumors are generally locally
invasive and have microscopic projections that extend
through the pseudocapsule, thereby predisposing to local
recurrence after conservative surgical excision.10,12
Treatment of soft tissue sarcomas has included surgery
alone, RT alone, chemotherapy, or a combination of modalities.13-24 Marginal surgical resection followed by postoperative RT yields the best results, providing a median survival
time of 1851 days and a time to local recurrence of >798
days.24 In some cases, this aggressive approach is not possible because of tumor location or size or because of concurrent disease. Palliative RT may offer some benefit in this
setting, with the goal being to delay tumor progression and
improve quality of life.
Four-Fraction Radiotherapy for Soft Tissue Sarcoma
101
The purpose of this retrospective study was to assess the
efficacy of a four-fraction palliative RT protocol in dogs
with macroscopic soft tissue sarcomas.
Materials and Methods
Study Animals
The RT database at the University of Wisconsin-Madison
Veterinary Medical Teaching Hospital (UW-VMTH) was
searched for all dogs that had been started on a course of
palliative RT for macroscopic soft tissue sarcoma. Cases
were included if they met the following criteria: adequate
staging (including histopathological diagnosis and tumor
measurements), intent to treat with four-fraction RT, and
sufficient follow-up information. Medical records were
reviewed for signalment, laboratory data (including complete blood count [CBC], serum biochemical profile, urinalysis, histopathological tumor diagnosis), clinical staging,
pretreatment tumor volume, treatment methods (radiation
protocol, overall duration of radiation, chemotherapy, surgery, and any other medications), radiation side effects,
underlying reason for the owner seeking RT, owner satisfaction, and tumor response to RT.
Side effects for dogs treated after October 2001 were formally graded according to the Veterinary Radiation Therapy
Oncology Group acute RT morbidity scoring scheme,25 and
results were recorded for each dog throughout therapy and
at follow-up with UW-VMTH. This same scoring scheme
for acute and late toxicity was also retrospectively applied
(based on notations within the medical record) to all dogs
treated before October 2001, even though a standardized
scoring scheme was not in effect at that time.
Tumor size was measured at the initial consultation, at
the administration of each fraction, and at various intervals
after RT had been completed. Tumor measurements were
not always recorded by the same individual. Tumor volume
was calculated according to the formula v = π/6(lwh), in
which l, w, and h represent diameters in three mutually
orthogonal planes. Individual dimensions were recorded at
the time of each radiation treatment, but tumor volume was
more consistently recorded during follow-up. Therefore,
volume estimates were used for evaluation of response.
A “complete response” was defined as complete disappearance of all measurable tumor. A “partial response” was
defined as >50% reduction in tumor volume. “No response”
was defined as <50% reduction and ≤25% increase in tumor
volume. Progressive disease was defined as a >25%
increase in tumor volume. Overall response rate was
defined as the percentage experiencing complete or partial
response.
Follow-up information was obtained through rechecks at
UW-VMTH, through standardized satisfaction postcards
sent to owners after RT, or through telephone communication with owners and/or referring veterinarians. Postcards
provided information on owner satisfaction with the RT,
recovery from side effects, time to recurrence, and survival
Responses and Toxicities
102
JOURNAL of the American Animal Hospital Association
time. No formal recheck schedule was consistently followed,
but the recommended follow-up schedule was 2 to 4 weeks
after therapy and then every 2 to 3 months thereafter, unless
problems arose.
The “progression-free” interval was defined as the time
between the start of RT and documented progression. If the
date of tumor progression was unknown, then dogs were
censored from progression-free analysis at the point of last
known nonprogressive follow-up. Survival times were calculated from the start of RT until documented date of death.
Dogs were censored from survival analysis if their deaths
were unrelated to the tumor, if they were lost to follow-up,
or if a cause of death was unknown.
The median progression-free interval and survival time
were calculated using the Kaplan-Meier product-limit
method.26 Response to treatment and tumor size were evaluated for their association with these outcomes. Differences
in progression-free interval and survival time between
groups were compared using the logrank test. A two-sided
Fisher’s exact test was used to compare the likelihood of
response associated with receiving or not receiving concurrent chemotherapy and larger versus smaller (than the median) tumor volume. Statistical calculations were performed
using a commercial statistical software package.b A P value
<0.05 was considered significant in all analyses.
Statistics
The database included 18 dogs with soft tissue sarcoma
treated with palliative RT between March 1995 and January
2002. Results of complete blood work, urinalysis, thoracic
radiographs, and histopathology were available for all dogs.
Additional diagnostics included computed tomography
(CT) scan (n=4), abdominal ultrasound (n=5), magnetic resonance imaging (MRI) (n=1), echocardiogram (n=1), and
skull (n=2) or pelvic (n=1) radiographs. Two of the 18 dogs
were excluded from the study because of incomplete medical records.
Of the 16 dogs included in this study, 12 were neutered
males and four were spayed females. The ages ranged from
3 to 15 years, with a median of 10 years and a mean (± standard deviation [SD]) of 9.9 (±3) years. Breeds included
golden retriever (n=3), Labrador retriever (n=3), mixedbreed dog (n=3), Siberian husky (n=2), German shepherd
dog (n=2), Shetland sheepdog (n=1), toy poodle (n=1), and
Doberman pinscher (n=1).
Results
Soft tissue sarcomas consisted of various histiotypes located in several areas of the body [see Table]. Pretreatment
tumor volumes ranged from 5.65 cm3 to 1754 cm3, with a
median of 81 cm3 and a mean (± SD) of 260 (±449) cm3.
Records indicated that 12 of the 16 owners had sought therapy because of pet discomfort related to the sarcoma. The
reason behind palliative therapy was not specifically documented in the other four cases, but medical records suggest-
Tumor Characteristics
May/June 2008, Vol. 44
ed that these four tumors were treated to slow the progression of the tumor and to alleviate presumed discomfort. In
all cases, potentially curative therapy was offered to the
owners. Such therapy included amputation, body wall
resection, complete surgical excision, and/or definitive RT.
All owners declined definitive treatment and elected palliative therapy.
The RT protocols consisted of manual methods using single
or parallel opposed fields, with a 3-cm margin surrounding
the palpable edge of the tumor (if possible). Computed
tomography scans were used when available to help estimate field size and depth of treatment, but true image-based
computer planning was not performed. When feasible, critical structures such as eyes, nasal planum, and lungs were
blocked from inclusion in the field. For appendicular sites,
a narrow portion of tissue was spared to decrease the risk of
radiation-induced lymphatic obstruction. The total dose of
radiation prescribed to the tumor was 32 Gy to isocenter,
delivered as one 8-Gy fraction on days 0, 7, 14, and 21. All
fractions were administered using a cobalt teletherapy unit.a
Treatment Protocol
In addition to four-fraction RT, 12 dogs received other therapy before, during, or after RT [see Table]. Tumors continued to progress in all 12 dogs in the face of therapy given
before RT. Three dogs had received concurrent doxorubicin/cyclophosphamide chemotherapy at standard dosages
at 3-week intervals for four cycles. Medical records of these
three dogs suggested that chemotherapy was administered to
help improve tumor response to RT. Further therapy at the
time of tumor progression consisted of piroxicam (n=3),
investigational Phenstatin phosphate chemotherapy (n=1),
endostatin gene therapy and genetically modified
Salmonella (n=1), additional radiation (n=2), or chemotherapy (n=1).
Other Therapies
Radiation therapy was given to 15 of the 16 dogs on days 0,
7, 14, and 21. The remaining dog (case no. 7; see Table)
became clinically ill secondary to neutropenia induced by
chemotherapy, so the first and second fractions of radiation
were delivered 2 weeks apart. Two of the 16 dogs had
achieved a partial response by the fourth radiation dose, and
one dog had stable disease at that time. Radiation was well
tolerated, with all dogs continuing to display normal or subjectively improved attitudes, appetites, and energy levels.
Mild, acute side effects were noted during therapy.
Grades of acute toxicity were assigned prospectively to one
hospitalized dog (using standardized toxicity criteria), but
all other cases were graded retrospectively. Two dogs developed grade-1 skin desquamation; three dogs developed
grade-2 moist desquamation; and three dogs developed
grade-2 oral mucositis. All eight of these dogs were
rechecked within 2.5 weeks of completion of RT, at which
time all acute side effects had resolved. Four of the eight
Response to Treatment
Tumor Histotype
Histiocytic sarcoma
Fibrosarcoma
Hemangiopericytoma
Fibrosarcoma
Hemangiopericytoma
Hemangiosarcoma
Anaplastic sarcoma
Hemangiopericytoma
Hemangiopericytoma
Hemangiopericytoma
Liposarcoma
Fibrosarcoma
Dog
11
12
13
14
15
16
17
18
19
10
11
12
Oral cavity
Trunk
Thoracic limb
Thoracic limb
Thoracic limb
Pelvic limb
Lateral thorax
Thoracic limb
Head
Trunk
Pelvic limb
Thoracic limb
Location
Endostatin gene
therapy
Incomplete surgical
excision (twice
attempted)
Incomplete surgical
excision
Incomplete surgical
excision
Preradiation
Therapy
Cyclophosphamide
+ doxorubicin\
Cyclophosphamide
+ doxorubicin\
Cyclophosphamide
+ doxorubicin\
Concurrent
Chemotherapy
Stable disease
Piroxicam‡
Radiation therapy¶
Endostatin gene therapy;
genetically modified
Salmonella
Phenstatin phosphate
chemotherapy
Radiation therapy§
Piroxicam‡
Rose Bengal
Partial response
Doxil† (one dose)
Four-Fraction Radiotherapy for Soft Tissue Sarcoma
(Continued on next page)
Stable disease
Partial response
Stable disease
Partial response
Partial response
Partial response
Complete response
Stable disease
Partial response
Stable disease
Tumor Response
to Radiation
Postradiation
Therapy
Tumor Characteristics and Adjunctive Therapies for 16 Dogs Receiving a Four-Fraction Radiotherapy Protocol
for Treatment of Measurable Soft Tissue Sarcomas*
Table
May/June 2008, Vol. 44
103
Fibrosarcoma
Fibrosarcoma
Myxosarcoma
Spindle cell sarcoma
13
14
15
16
Thoracic limb
Head
Head
Oral cavity
Location
Cyclophosphamide
+ doxorubicin\
(one cycle only)
Endostatin gene
therapy; genetically
modified Salmonella
Preradiation
Therapy
Concurrent
Chemotherapy
Partial response
Stable disease
Piroxicam‡
Piroxicam‡
Stable disease
Stable disease
Tumor Response
to Radiation
Postradiation
Therapy
* Note: All tumors that were surgically excised had recurred by the time of radiation therapy. All postradiation treatments were instituted at the time of documented tumor progression.
† Doxil: 1 mg/kg intravenously q 3 wks
‡ Piroxicam: 0.3 mg/kg per os q 24 h
§ Radiation therapy: Two fractions of 5 Gy delivered 1 wk apart
\ Cyclophosphamide: 150 mg/m2 intravenously q 3 wks; doxorubicin: 30 mg/m2 intravenously q 3 wks
¶ Radiation therapy: Two fractions of 6.5 Gy delivered 1 wk apart
Tumor Histotype
Dog
Tumor Characteristics and Adjunctive Therapies for 16 Dogs Receiving a Four-Fraction Radiotherapy Protocol
for Treatment of Measurable Soft Tissue Sarcomas*
Table (cont’d)
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May/June 2008, Vol. 44
May/June 2008, Vol. 44
dogs were reevaluated at the UW-VMTH, and the remaining four were evaluated by referring veterinarians.
Each of the 16 dogs was evaluated at some point after
therapy by a referring veterinarian, with five of the 16 dogs
rechecked at 14 to 19 days after completion of therapy. Of
the 16 cases, 13 were also reevaluated at the UW-VMTH at
some time period between 2 weeks (four dogs) and 8
months (one dog) after treatment. Recheck evaluations were
recommended at regular intervals (i.e., 2 weeks, then 1
month, then every 3 months), but few dogs were consistently returned for evaluation, and the level of follow-up varied.
For example, of the 13 dogs reevaluated at UW-VMTH, one
was evaluated at 2 and 4 weeks; two were evaluated at 1
month, with repeat evaluations at 2-month intervals; and
one was evaluated at 3 and 5 months. All other cases were
rechecked at UW-VMTH no more than once.
The overall objective response rate was 50% and included seven partial and one complete response. Three dogs
experienced a 30% to 40% reduction in tumor size but did
not fully meet the criteria for objective response. The
remaining five dogs had static tumors that did not change
measurably in size. None of the dogs developed progressive
disease during the course of therapy, and eight dogs experienced stable disease for a median of 140 days.
The dog that experienced a complete response had been
diagnosed with a cutaneous hemangiosarcoma located over
the left ventral thorax. This dog received chemotherapy
concurrent with RT. The tumor did not progress for 224
days, but the dog was euthanized at 253 days because of
local recurrence and ulceration of the tumor.
Nine of the 16 owners were pleased with the clinical
responses achieved through treatment, with three owners
reporting significant improvement of lameness in their
dogs. One owner expressed mild displeasure associated
with the side effects (oral mucositis) but did not regret the
decision to pursue RT. In the remaining cases, owner satisfaction was not documented.
No variables were statistically associated with response
to RT. All three dogs treated with concurrent chemotherapy
achieved an objective response, but this finding was not statistically significant (P=0.10), likely due to the small sample size. The small sample size also precluded the statistical
evaluation of whether treatment before RT affected the
response rate.
The median progression-free interval was 155 days, with
a range of 72 to 460 days [see Figure]. Four dogs were censored from progression-free analysis because of lack of follow-up regarding date of documented progression. Six
(48%) dogs were progression free at 6 months, and two
(16%) dogs were still progression free at 1 year.
Twelve (75%) dogs were alive at 6 months, and six
(37%) dogs were still alive at 12 months. The overall median survival time was 309 days, with a range of 73 to 600
days [see Figure]. Three dogs were censored from survival
analysis at the time of death from causes completely unrelated to the tumor. Among these three deaths, one dog with
a truncal hemangiopericytoma died acutely after collapsing;
Four-Fraction Radiotherapy for Soft Tissue Sarcoma
105
Figure—Progression-free interval and overall survival time
for dogs with soft tissue sarcomas treated with radiation
therapy. Three dogs were censored from progression-free
interval analysis because of lack of follow-up pertaining to
date of documented progression. Four dogs were censored
from survival analysis at the time of death because of
causes of death unrelated to their tumors.
one dog treated for a forelimb hemangiopericytoma was
euthanized for paraparesis and fecal incontinence; and one
dog with a forelimb hemangiopericytoma died secondary to
unregulated diabetes mellitus and hyperadrenocorticism.
The median survival time of the eight dogs responding to
RT was 218 days, and the median survival time of dogs not
responding was 416 days. This difference was not statistically significant (P=0.34). The three dogs that received concurrent doxorubicin and cyclophosphamide experienced
survival times of 253 days, 309 days, and 373 days.
This is the first report describing the response to a four-fraction protocol in dogs with measurable soft tissue sarcomas.
The literature on coarse-fractionated RT for soft tissue sarcomas is sparse, although various reports have emerged in
the past 13 years. A recent report described a coarse-fractionated protocol consisting of three 8-Gy fractions given
either weekly or on days 0, 7, and 21.30 Fifteen dogs with
either fibrosarcoma or hemangiopericytoma were treated,
and 13 (87%) of the 15 dogs achieved stable disease for a
median of 263 days.30 Only one partial response was noted
in this study. Time to progression and survival time were
longer in this study (263 days and 332 days, respectively)30
than in the authors’ study (155 days and 309 days, respectively), but this may be an artifact caused by favorable case
selection in the former study and by more severe, refractory disease in this study’s population of dogs. The median
tumor volume in this study was 81 cm3, while that in the
previous report was 75 cm3.30 In addition, only five tumors
in the previous report had been surgically resected, and 10
were treated solely with primary coarse-fractionated radiotherapy.30 Recurrent tumors may be more difficult to treat,
and many of the dogs in the authors’ study had received
Discussion
106
JOURNAL of the American Animal Hospital Association
other forms of treatment before RT, which is often the case
with advanced malignancies.10
In another report, 16 dogs were irradiated for advanced
nonskeletal tumors (including melanomas and sarcomas)
using three fractions of 8 Gy each.1 The protocol was tolerated very well, with quick pain relief and minimal side effects.
These dogs survived for up to 557 days after treatment.1
In the authors’ study, 50% of dogs responded to therapy,
and dogs remained progression free for a median of approximately 5 months. Limb function was definitively improved
after RT in three dogs; two of these dogs were partial
responders, but the third dog did not have a measurable
response. All dogs tolerated RT well, with minimal and
acceptable acute side effects. Late effects were not noted in
any of the 16 dogs. However, the median survival time was
10 months, and late effects may not have become clinically
apparent within that time period.
The authors chose a protocol consisting of 8-Gy fractions
administered once weekly, based on a recommended fractional dose of 8 Gy for optimal palliation of bone metastasis in people.28,29 Use of this fractionation scheme has been
standard practice at UW-VMTH, even though a 0-7-21-day
protocol has been used in previous studies.1,30 A dose of 8
Gy is estimated to kill approximately 70% to 80% of the
tumor population.27
Radiation protocols can be compared using a formula
known as the “biological equivalent dose” (BED), which
estimates effective doses to tissues.5 Assuming α/β ratios of
10 for acute effects and 3 for late effects, the BED for the
authors’ four-fraction protocol is 57.6 Gy10 for acute effects
and 117.3 Gy3 for late effects. By comparison, using 8-Gy
fractions in the published 0-7-21-day protocol for advanced
malignancies and soft tissue sarcomas yields BEDs of 43.2
Gy10 for acute effects and 88 Gy3 for late effects.1,30 These
findings suggest that the authors’ four-fraction protocol may
have greater efficacy against acutely responding tissue such
as tumor, but that late-responding tissues will also be more
affected (i.e., greater probability of late side effects).
Coarsely fractionated protocols can certainly cause significant late tissue damage and (if used inappropriately) can
eventually impact quality of life during a durable
response.5,7 However, some radiation oncologists may be
less concerned with late effects when dealing with palliative
therapy, because dogs undergoing such treatment do not live
long enough to experience late radiation effects. None of the
dogs in this study suffered any reported late effects (even
given the higher effective dose for late-responding tissues),
which was most likely a result of the relatively short survival time. The incidence of late effects possibly would
have been higher if the dogs had survived longer.
Applying the BED formula to a published definitiveradiation protocol of 19 fractions of 3 Gy each yields effective doses of 74 Gy10 for acute effects and 114 Gy3 for late
effects.24 This definitive protocol, which is prescribed to
cure microscopic disease, yields a higher effective dose for
acute effects (tumor) and a lower BED for late effects than
the protocol the authors used to treat bulky, nonresectable
May/June 2008, Vol. 44
soft tissue sarcomas. This highlights the fact that coarsefractionated protocols are not meant to replace definitive,
protracted RT because of the potential negative impact on
normal structures associated with palliative, coarse-fractionated procedures.
Large soft tissue sarcomas can cause significant discomfort and impairment in normal function. Analgesics are
often used to maintain quality of life when other therapeutic options are not feasible. Curative surgery with or without
RT may not be feasible because of tumor size and location.
Alternative management methods for nonresectable soft tissue sarcomas are needed. Preoperative, definitive radiation
protocols may prove beneficial by shrinking the tumor to a
resectable volume. Additionally, amputation may be curative for dogs with low- or intermediate-grade soft tissue sarcomas of the distal limb.
The use of chemotherapy for soft tissue sarcoma is somewhat controversial, because chemotherapy in combination
with radiation has not been shown to definitively improve
response or survival, although it may provide palliation in
the case of measurable tumors.10,16,31 The use of chemotherapy in combination with palliative RT has not been assessed
but may potentially delay onset of systemic disease and
improve/maintain quality of life in the case of metastatic
tumors. An alternative view is that chemotherapy has the
potential to make animals ill, and it may not significantly
impact the disease process underlying patient discomfort.
Limitations of this study included the small sample size,
the lack of a control group, the observational (i.e., nonrandomized) and retrospective design, and variable use of adjuvant therapies. Only 16 dogs were evaluated, and these
could not be compared to a similar group of dogs that did
not receive RT. Bias (e.g., confounding or selection bias) is
also a potential problem in any observational study (especially a retrospective one), although it is difficult to determine if such bias actually occurred. Owners of dogs in
profound discomfort with advanced disease may be less
likely to opt for RT, and it is possible that the dogs in the
authors’ study population were healthier than the average
dog with soft tissue sarcoma. In other instances, definitive
treatment of operable tumors may be declined for various
reasons. In these cases, coarsely fractionated RT serves as
palliative therapy for dogs experiencing poor quality of life,
rather than as a true substitute for definitive treatment.
It is not known whether the 16 dogs in this study would
have survived as long as they did without palliative therapy.
However, early euthanasia was a real possibility in these
cases, given that most (11 of 16) owners sought treatment
for deteriorating quality of life. The retrospective nature of
this study made it difficult to adequately evaluate pain relief
and return to function among treated dogs, given that tumor
size and response to therapy were documented more thoroughly than resolution of discomfort.
The authors also may not have captured the full range of
improvement among treated dogs. Some tumors can take
months to shrink, so it is possible that tumor volume may
have continued to decrease even among dogs that did not
May/June 2008, Vol. 44
achieve an objective response during the study and followup periods. Tumor volume was not consistently measured
during reevaluation, but it is clear from time-to-progression
data that any additional shrinkage was temporary.
As with any retrospective study, the authors did not have
control over numerous treatment-related variables, frequency of reevaluation, etc. One source of concern is the fact that
most dogs were treated with a wide variety of additional
therapies before or after RT. However, only three dogs had
concurrent chemotherapy that might have affected assessment of response to RT. While variable chemotherapeutic
regimens, investigational agents, and prior surgical excisions were performed before RT, a 50% response rate was
still achieved.
It is impossible to know with certainty whether pretreatment had a substantive impact on response or progressionfree interval. Various treatment regimens, such as gene
therapy or prior surgery, certainly may have altered tumor
blood supply or gene expression. Such concurrent treatments may have also modulated “bystander effects” associated with RT, thereby modifying inherent tumor response to
ionizing radiation. Chemotherapy may act in conjunction
with RT, so it is also conceivable that dogs receiving
chemotherapy had improved responses to RT. In this regard,
it should be noted that the three dogs receiving concurrent
doxorubicin and cyclophosphamide had survival times
equal to or better than the median. Interestingly, all three
dogs had objective antitumor responses. The role of concurrent chemotherapy would be an interesting subject for a
future prospective study, but its role in the present set of
dogs cannot be determined.
Another issue of concern is that dogs were treated with
manual setups based on visual assessment of the tumor.
Image-based planning (generally CT-based) allows better
determination of the targeted tumor volume, and it may help
limit the volume of surrounding normal tissue that is irradiated.32 Computerized treatment planning was not performed in any of the dogs in this study, although CT images
were used to help estimate tumor volume. Computerized
tomography was done in 25% of dogs for evaluation of
invasiveness and as a guide for potential surgery. Imaging
was not done in the remaining 75% of dogs. It is possible
that visual and palpable evaluation underestimated the
extent of tumor in these dogs, even given the 3-cm margin.
Computerized treatment planning individualized for each
dog may have improved local control.
The effect of postradiation treatments on overall survival
is impossible to evaluate effectively. Radiation therapy may
cause cellular damage and death for months after delivery,
and it is theoretically possible that additional postradiation
therapies acted synergistically to enhance tumor control.
However, the fact remains that the 50% response rate
among the dogs in this study was not durable beyond a
median of 5 months.
Interestingly, dogs experiencing stable disease had a
median survival time of 416 days, while partial/complete
responders survived for only a median of 218 days. This dif-
Four-Fraction Radiotherapy for Soft Tissue Sarcoma
107
ference was not significant, so it may have been a chance
occurrence. However, it should be noted that four of the
nonresponders had tumors located on the extremities.
Perhaps tumors on the extremities were better compensated
for than tumors located on the trunk or within the oral cavity. Alternatively, such tumors possibly were innately less
proliferative than other tumors.
Aggressive local therapy remains the standard of care for
treatment of soft tissue sarcomas and often involves a combination of surgery and definitive RT. However, results of
this study support the use of coarsely fractionated RT as a
viable therapeutic option for soft tissue sarcomas, if definitive treatment (e.g., surgery with or without curative RT) is
not elected or is not expected to improve local control.
Furthermore, RT delivered as four weekly fractions may be
attractive to some owners because of the fewer number of
visits and less time required for hospitalization.
Such short-course, high-dose protocols result in a relatively high risk for late radiation side effects. This fact
should be considered and explained to owners, particularly
in cases where animals may be better served by protocols
intended to provide a cure. However, clearly nonresectable,
large, bulky tumors may respond well to coarse-fractionated RT over the short term. The coarse-fraction protocol was
well tolerated by all dogs in this study and may offer an
opportunity for temporary relief of pain and return to function. The ideal protocol to achieve good local control and
amelioration of clinical signs has yet to be determined.
Conclusion
a Theratron 780; Atomic Energy of Canada, Kanata, Ontario, K2K 1X8,
Canada
b Prism 4.0b; GraphPad Software, San Diego, CA 92130
Footnotes
11. Bateman KE, Catton PA, Kruth SA. 0-7-21 Radiation therapy for the
palliation of advanced cancer in dogs. J Vet Intern Med 1994;8:
394-399.
12. Thrall DE, LaRue SM. Palliative radiation therapy. Semin Vet Med
Surg (Small Anim) 1995;10:205-208.
13. McNiel EA, LaRue SM. Principles of adjunctive radiation therapy.
Clin Tech Small Anim Pract 1998;13:33-37.
14. McEntee MC. Principles of adjunct radiotherapy and chemotherapy.
Vet Clin North Am Small Anim Pract 1995;25:133-148.
15. Hall EJ, Giaccia AJ, eds. Time, dose, and fractionation in radiotherapy. In: Radiobiology for the Radiologist. 6th ed. Philadelphia:
Lippincott Williams & Wilkins, 2006:378-397.
16. Hill RP, Bristow RG. The scientific basis of radiotherapy. In: The
Basic Science of Oncology. 4th ed. New York: McGraw-Hill,
2005:289-321.
17. Hall EJ, Giaccia AJ, eds. Clinical response of normal tissues. In:
Radiobiology for the Radiologist. 6th ed. Philadelphia: Lippincott
Williams & Wilkins, 2006:327-348.
18. Thrall DE. Biologic basis of radiation therapy. Vet Clin North Am
Small Anim Pract 1997;27:21-35.
19. Harris D, King GK, Bergman PJ. Radiation therapy toxicities. Vet
Clin North Am Small Anim Pract 1997;27:37-46.
10. Liptak JM, Forrest LJ. Soft tissue sarcomas. In: Withrow SJ, Vail
DM, eds. Small Animal Clinical Oncology. 4th ed. St Louis:
Saunders, 2007:425-454.
References
May/June 2008, Vol. 44
11. Fajardo LF, Berthrong M, Anderson RE, eds. Radiation Pathology.
Oxford: Oxford University Press, 2001.
12. Thrall DE, Gillette EL. Soft tissue sarcomas. Semin Vet Med Surg
(Small Anim) 1995;10:173-179.
13. Kuntz CA, Dernell WS, Powers BE, et al. Prognostic factors for surgical treatment of soft tissue sarcomas in dogs: 75 cases (19861996). J Am Vet Med Assoc 1997;211:1147-1151.
14. Bostock DE, Dye MT. Prognosis after surgical excision of canine
fibrous connective tissue sarcomas. Vet Pathol 1980;17:581-588.
15. McChesney SL, Withrow SJ, Gillette EL, et al. Radiotherapy of soft
tissue sarcomas in dogs. J Am Vet Med Assoc 1989;194:60-63.
16. Ogilvie GK, Obradovich JE, Elmslie RE, et al. Efficacy of mitoxantrone against various neoplasms in dogs. J Am Vet Med Assoc
1991;198:1618-1621.
17. Moore AS. Recent advances in chemotherapy for nonlymphoid
malignant neoplasms. Compend Contin Educ Pract Vet
1993;15:1039-1050.
18. Dernell WS, Withrow SJ, Straw RC, et al. Intracavitary treatment of
soft tissue sarcomas in dogs using cisplatin in a biodegradable polymer. Anticancer Res 1997;17:4499-4506.
19. Henry CJ, Buss MS, Potter KA, et al. Mitoxantrone and cyclophosphamide combination chemotherapy for the treatment of various
canine malignancies. J Am Anim Hosp Assoc 1999;35:236-239.
20. McKnight JA, Mauldin GN, McEntee MC, et al. Radiation treatment
for incompletely resected soft tissue sarcomas in dogs. J Am Vet
Med Assoc 2000;217:205-210.
21. Evans SM. Canine hemangiopericytoma. Vet Radiol 1987;28:13-16.
22. Postorino NC, Berg RJ, Powers BE, et al. Prognostic variables for
canine hemangiopericytoma: 50 cases (1979-1984). J Am Anim
Hosp Assoc 1988;24:501-509.
Four-Fraction Radiotherapy for Soft Tissue Sarcoma
108
23. Thrall DE, Prescott DM, Samulski TV, et al. Radiation plus local
hyperthermia versus radiation plus the combination of local and
whole-body hyperthermia in canine sarcomas. Int J RT Oncol Biol
Phys 1996;34:1087-1096.
24. Forrest LJ, Chun RC, Adams WM, et al. Postoperative radiotherapy
for canine soft tissue sarcoma. J Vet Intern Med 2000;14:578-582.
25. Ladue TA, Klein MK. Toxicity criteria of veterinary radiation therapy oncology group. Vet Radiol Ultrasound 2001;42:475-476.
26. Kaplan EL, Meier P. Nonparametric estimation from incomplete
observations. J Am Stat Assoc 1958;53:457-481.
27. LaRue SM, Gillette EL. Radiation therapy. In: Withrow SJ,
MacEwen EG, eds. Small Animal Clinical Oncology. 3rd ed. New
York: WB Saunders Co, 2001:119-137.
28. Hurley RA, Richter W, Torrens L. The results of radiotherapy with
high pressure oxygen in carcinoma of the pharynx, larynx, and oral
cavity. Br J of Radiology 1972;45:98-109.
29. Bone Pain Trial Working Party. 8 Gy single fraction radiotherapy for
the treatment of metastatic skeletal pain: randomized comparison
with a multifraction schedule over 12 months of patient follow up.
Radiother Oncol 1999;52:101-109.
30. Plavec T, Kessler M, Kandel B, et al. Palliative radiotherapy as treatment for non-resectable soft tissue sarcomas in the dog – a report of
15 cases. Vet Comparative Oncol 2006;4:98-103.
31. Selting KA, Powers BE, Thompson LJ, et al. Outcome of dogs with
high grade soft tissue sarcomas treated with and without adjuvant
doxorubicin chemotherapy: 38 cases (1996-2004). J Am Vet Med
Assoc 2005;227:1442-1448.
32. Bentel GC. Radiation Therapy Planning. 2nd ed. New York:
McGraw-Hill, 1996:16-31.
Lumbosacral Intervertebral Disk Disease
in Six Cats
Medical records of six cats diagnosed with lumbosacral intervertebral disk disease were
reviewed. Clinical signs included reluctance to jump, low tail carriage, elimination outside the
litter box, reluctance to ambulate, pelvic-limb paresis, urinary incontinence, and constipation.
All cats had lumbosacral hyperpathia on palpation. Computed tomography in four cats
revealed evidence of extradural spinal cord compression at the seventh lumbar (L7) to first
sacral (S1) vertebral interspace. Compression was confirmed via myelography in three of
these four cats, with confirmation in the fourth cat at the time of decompressive laminectomy.
Each of the six cats underwent dorsal decompressive laminectomy at the L7 to S1 interspace.
Postoperative clinical follow-up lasted 3 to 35 months, with most cats having excellent outcomes. J Am Anim Hosp Assoc 2008;44:109-115.
Jennipher E. Harris, DVM, MS
Sarit Dhupa, BVSc,
Diplomate ACVS
RS
Intervertebral disk disease (IVDD) within the lumbosacral spine is a frequently reported and documented clinical disease syndrome in dogs, but
little is known about lumbosacral IVDD in cats. Disk degeneration and
protrusion occur commonly in cats and are routine incidental findings at
necropsy.1,2 However, IVDD in cats is not usually accompanied by recognized clinical signs.1,2
To the authors’ knowledge, only one clinical case of feline lumbosacral IVDD has been reported.12 Therefore, this retrospective study
was performed to evaluate clinical signs and surgical outcomes in cats
diagnosed with lumbosacral IVDD to further understand this disease
process in domestic cats.
Introduction
Medical records of feline cases of lumbosacral IVDD that were referred
to California Veterinary Specialists between October 2002 and October
2006 were reviewed. Inclusion criteria consisted of 1) diagnosis of lumbosacral IVDD based on the results of myelography, computed tomography (CT), or confirmation at the time of surgery and 2) subsequent
lumbosacral decompression. Age, sex, breed, body weight, clinical history, indoor/outdoor status, presenting clinical signs, cerebrospinal fluid
analysis, radiographic findings, surgical findings, and outcome for each
cat were recorded if available. Follow-up surveys were administered to
the clients of all cases, and residual clinical signs were recorded.
All cases were assessed for degree of “functional recovery,” which
was based on regaining the ability to walk, fecal and urinary continence,
and absence of persistent back pain.4 Recovery was rated “excellent” if
the owner felt that the cat had complete resolution of lumbosacral hyperpathia, with appropriate ambulation and elimination. Recovery was rated
“good” if clinical signs were improved but mild residual lumbosacral
hyperpathia was seen. Recovery was rated “fair” if significant clinical
signs persisted, but quality of life was still acceptable. Recovery was
Materials and Methods
From the Surgical Department,
California Veterinary Specialists,
100 North Rancho Santa Fe Road,
Suite 133, San Marcos,
California 92069.
JOURNAL of the American Animal Hospital Association
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JOURNAL of the American Animal Hospital Association
May/June 2008, Vol. 44
“poor” if clinical signs did not resolve and quality of life
was unacceptable.
For the purpose of the current study, Hansen’s type I disk
disease was defined as disk extrusion into the spinal canal
that causes a focal compressive myelopathy. Hansen’s type
II disk disease included protrusion of disk material within
an intact annulus, resulting in a compressive myelopathy.5
Spinal hyperpathia was defined as an unpleasant, painful
response to a noxious stimulus (especially if repeated). Such
a response is characterized by delay, overreaction, and
aftersensation.5
Out of a total of 11,151 cats seen within the study time
frame, six cats were diagnosed with lumbosacral IVDD,
suggesting a 0.05% incidence in the authors’ hospital population. Descriptive characteristics for the six cases are presented in Table 1. The cases were equally divided between
spayed females and castrated males, with domestic shorthair
(DSH) being the most common breed. The mean age was
12.6 years (median 12 years), and the mean body weight
was 6.5 kg [Table 1]. All six cats were kept strictly indoors.
The most common signs from the clinical histories were
reluctance to jump, which was observed in all cats, and low
tail carriage, which was seen in three cats [Table 2]. All cats
were ambulatory on presentation and had significant pain
when direct digital pressure was applied to the lumbosacral
region. All five cats with a tail had pain on tail hyperextension (hyperextension was not possible in the Manx). Digital
rectal evaluation was not performed in any conscious cat.
Significant ancillary findings included severe bilateral stifle
osteoarthritis, diabetes mellitus, and chronic renal failure
(case no. 1); bilateral medially luxating patellae (case no.
4); and obesity, a ruptured cranial cruciate ligament, and
cystic calculi (case no. 6).
Cerebrospinal fluid was collected from the cerebellomedullary cistern in three of the six cats; all cell counts
and protein concentrations were within the reference ranges.
The CT scans, which were performed in four cats, did not
reveal any articular process thickening or sclerosis. Two of
the four CT scans suggested a ventral compressive lesion of
the cauda equina [Figures 1, 2]. The CT scan of case no. 3
revealed lumbosacral caudal malformation and dural malformation, which were confirmed by myelography.
The CT scan for case no. 4 revealed stenosis of the spinal
canal within a lumbosacral transitional vertebra at the seventh lumbar (L7) to first sacral (S1) interspace [Figure 3].
Survey spinal radiographs of this cat confirmed that a transitional lumbosacral vertebra was incompletely fused to the
remainder of the sacrum [Figure 4]. Myelography confirmed mild ventral compression at the L7 transitional lumbosacral vertebra [Figure 5].
Dorsal decompressive laminectomies were successfully
performed at the L7 to S1 interspace in all cats. Case no. 4
also underwent right-sided medial patellar stabilization during the same anesthetic/surgical period. One cat had evidence of extruded disk material within the spinal canal,
Results
Figure 1—A computed tomographic (CT) image of case
no. 5 with mild caudal equina compression at the lumbosacral junction.
Figure 2—A CT image of case no. 6 with mild loss of
epidural fat on the right side.
Figure 3—A CT image of case no. 4 with narrowing of the
vertebral canal within the body of the transitional lumbosacral vertebra.
consistent with Hansen’s type I disk disease. Five cats had
no obvious disk extrusion, but one of these had a Hansen’s
type II disk protrusion.
A preoperative dose of methylprednisolone sodium succinatea (30 mg/kg) was administered intravenously to each
cat at the start of the surgical procedure.6 No glucocorticosteroids were administered in the postoperative period.
12
15
7
13
12
2
3
4
5
6
*
†
‡
§
CM
17
1
DSH
DLH
DSH
Manx
DSH
Abyssinian
Breed†
10.4
6.5
6.3
4.7
6.8
4.5
Weight
(kg)
Reluctance to ambulate,
low tail carriage
Reluctance to jump,
low tail carriage
Straining to defecate,
low tail carriage
Urinary incontinence,
constipation
Reluctance to jump,
spinal hyperpathia
Reluctance to jump,
pelvic-limb paresis
Clinical Signs
CM=castrated male; SF=spayed female
DSH=domestic shorthair; DLH=domestic longhair
L7=seventh lumbar vertebra; S1=first sacral vertebra
R=survey radiographs; M=myelogram; CSF=cerebrospinal fluid analysis; CT=computed tomography
CM
SF
SF
SF
CM
Sex*
Case Age
No.
(y)
L7-S1
L7-S1
L7-S1
L7-S1
L7-S1
L7-S1
Site‡
CT
CT
R, M, CT, CSF
R, M, CT, CSF
R, M, CSF
R
Diagnostics§
Surgery
Surgery
Surgery,
patellar stabilization
Surgery,
cystostomy tube
Surgery
Surgery
Management
Clinical Findings in Six Cats With Lumbosacral Intervertebral Disk Disease
Table 1
3
3.5
15
23
35
9
Follow-up
(mo)
Excellent
Excellent
Excellent
Fair
Excellent
Fair
Outcome
May/June 2008, Vol. 44
Lumbosacral IVDD in Six Cats
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JOURNAL of the American Animal Hospital Association
May/June 2008, Vol. 44
Table 2
Clinical Histories of Cats With Lumbosacral Intervertebral Disk Disease
Case
No.
Clinical Histories
Duration
(mo)
Resolution
After Surgery
Cause of Death
1
Chronic renal failure
Bilateral stifle osteoarthritis
Weak in hind limbs
Hind-limb muscle atrophy
Unwilling to jump
Urine retention
24
17
12
12
8
6
None
None
Complete
Improved
Improved
Improved
Congestive heart failure
2
Unwilling to jump
Lethargy
Hiding
Back pain
Hind-limb lameness
6
2
2
2
1
Improved
Complete
Complete
Complete
Complete
N/A*
3
Recurrent constipation
Urinary incontinence
Unwilling to jump
1
1
1
Improved
None
Complete
N/A
4
Bilateral medial patellar luxation
Unwilling to jump
Back pain
Carrying tail low
Straining to defecate
Unknown
3
2
2
1
None
Complete
Complete
Complete
Complete
N/A
5
Fell 12 feet 7 years previously
Unwilling to jump
Decreased tail movement
Unwilling to walk
6
4
2
Complete
Complete
Complete
Right CCL rupture†
Difficulty sitting and squatting
Unwilling to walk
Unwilling to jump
Carrying tail low
Difficulty getting into litter box
2
2
2
2
2
1
None
Complete
Complete
Complete
Complete
Complete
6
N/A
N/A
* N/A=not applicable
† CCL=cranial cruciate ligament
Postoperative follow-up ranged from 3 to 35 months.
Clinical signs were markedly improved within 2 weeks in
four cats. Case no. 1 showed a slight improvement but had
continued urine retention that may have been caused by an
unrelated underlying disease process. Case no. 3 continued
to have urinary incontinence, so a permanent cystostomy
tube was placed during a later surgical procedure. Owner
survey responses revealed that the outcomes were “excellent” in four cats and only “fair” in two cats.
Little information has been published on IVDD in cats. To
the authors’ knowledge, only 30 cats with clinical IVDD
have been reported in the veterinary literature,3,7-12 with
only a single case report of lumbosacral IVDD.12 These 30
cats had a total of 32 localized lesions [Table 3],3,8,11,12
because two cats had evidence of compression at both the
13th thoracic (T13) to first lumbar (L1) vertebral interspace
and the fourth lumbar (L4) to fifth lumbar (L5) vertebral
Discussion
May/June 2008, Vol. 44
Lumbosacral IVDD in Six Cats
113
Table 3
Location of 32 Lesions Among Cases of
Feline Intervertebral Disk Disease Reported
in the Veterinary Literature
Figure 4—Survey spinal radiograph of case no. 4, showing
transitional lumbosacral vertebra.
Figure 5—Myelographic image of case no. 4, showing mild
ventral compression at the seventh lumbar (L7) transitional
vertebra.
interspace. Most (23) of these cats were affected in the thoracic or lumbar spine and underwent hemilaminectomy,
dorsal laminectomy, fenestration, or durotomy.3 Clinical
outcome data were available for 20 of these 23 cats, with 18
showing postoperative improvement.3
Clinically significant IVDD has been reported in cats
ranging in age from 1.5 to 17 years, with a mean age of 7
years.3,9 The cats in this study were substantially older
(mean 12.6 years), although still within the range reported
in the literature. Chondrodystrophic breeds of dogs suffer
from disk degeneration at an early age, whereas IVDD in
cats appears to be a condition of middle-aged animals.3
In one case report, a 5-year-old DSH presented with
acute hemiparesis and Horner’s syndrome. Magnetic resonance imaging (MRI) revealed left-sided dorsal displacement of the spinal cord at the third cervical (C3) to fourth
cervical (C4) vertebral interspace. The presumptive diagnosis was focal spinal cord edema with intervertebral disk
extrusion. With conservative treatment, this cat gradually
improved over 6 months.11
A retrospective study evaluated IVDD in six cats.10
Radiographic studies confirmed narrowed disk spaces, mineralized disks, and one or more extradural compressive
lesions in each cat. All intervertebral disk extrusions were in
the thoracolumbar spine. Hemilaminectomy was performed
in all cats, and the removed extradural material was confirmed as coming from degenerative disks. Neurological
Lesion Location
No. of Cats
C3-C4
1
C5-C6
2
T9-T10
1
T11-T12
1
T11-L1
1
T12-T13
2
T13-L1
7
L1-L2
2
L2-L3
1
L4-L5
7
L4-L6
1
L5-L6
3
L6-L7
2
L7-S1
1
recovery was good to excellent in five (83%) of the six cats.
It was concluded that IVDD in cats has many similarities to
IVDD in dogs, and healthy cats with acute disk extrusion
respond well to decompressive surgery.10
A retrospective study evaluated IVDD in 10 cats diagnosed over an 11-year period.9 All disk herniations occurred
in the thoracolumbar spine, with an increased incidence at
the L4 to L5 vertebral interspace. Eight cats had Hansen’s
type I disk disease, and two cats had Hansen’s type II disk
disease. Nine cats had radiographic imaging, which consisted of myelography (in eight cats), CT (in three cats), or both
(in two cats). The 10th cat was diagnosed at necropsy after
euthanasia for clinical signs. Seven cats had been treated
with corticosteroids before referral. Hemilaminectomy was
performed on seven cats, of which six had extruded disk
material in the spinal canal, and one had mild extradural
compression over a narrowed disk space. Two cats had minimal compression on myelography and improving clinical
signs, so they were conservatively managed with strict confinement for 4 weeks. Follow-up in seven cats revealed that
recovery was good in one conservatively managed cat but
poor in the other one, which never regained urinary or fecal
continence. Recovery was good to excellent in four cats
114
JOURNAL of the American Animal Hospital Association
undergoing surgery, but it was only fair in one ambulatory
cat because of fecal and urinary incontinence.9
Type I disk disease has been reported to occur more commonly in the thoracolumbar region of cats, which is consistent with findings in dogs.9 In the authors’ study, only one
cat had a type I IVDD, while five cats had type II disease.
The higher proportion of type II lumbosacral IVDD in the
cats of this study is consistent with that of lumbosacral
IVDD in dogs.
The single case of lumbosacral IVDD reported in the literature involved an 8-year-old, castrated male DSH.12 The
cat presented with a 2-day history of back pain, flaccid tail,
and urinary and fecal incontinence. Myelography, CT, and
an epidurogram revealed an L7 to S1 extradural lesion.
Exploratory surgery and histopathology confirmed a
Hansen’s type II disk protrusion. The cat regained neurological function by 6 weeks after surgery.
In dogs, the most common clinical presentation of lumbosacral disease is degenerative lumbosacral stenosis
(DLSS) with protrusion of a Hansen’s type II disk.13 This
occurs most commonly in middle-aged and medium- to
large-breed dogs, especially German shepherds.12-14
Causes of lumbosacral IVDD in dogs include thickening of
the dorsal annulus, mechanical instability of the lumbosacral junction, osteophyte formation within the spinal
canal, thickening of the articular facet joint capsule, thickening of the interarcuate ligament, and transitional vertebrae.13 Lumbosacral hyperpathia is the most consistent
clinical finding, and signs can be acute or chronic.
Diagnosis of DLSS may be difficult, and DLSS can be easily confused with chronic orthopedic conditions. The diagnostic evaluation includes general, orthopedic, and
neurological examinations, followed by radiographs and
advanced imaging techniques such as myelography, discography, epidurography, CT, and MRI. If a lesion is not
demonstrated by diagnostic imaging, exploratory surgery
may be indicated.
In a study of 131 dogs with DLSS treated by dorsal
laminectomy with fenestration, 56% were German shepherds, with a 2:1 male:female ratio.14 The most common
clinical signs were 1) pain on hyperextension of the tail or
hind limbs (98%); 2) reluctance or pain when jumping, rising from a prone position, or climbing stairs (92%); and 3)
lumbosacral pain (85%) and unwillingness to perform
extensive physical activity because of pain or stiffness
(85%). Overall, 79% of dogs returned to normal after surgery, and 93% showed clinical improvement within the follow-up period (26±17 months). The rate of recurrence based
on owner observation or clinical examination was 18%.14
The above results are similar to those reported in another study of 69 dogs with DLSS that underwent dorsal
laminectomy. The male:female ratio was 2.6:1, with
German shepherds as the most common breed (27% of
cases).15 Clinical signs were also similar and included
lower lumbar pain (77%); difficulty jumping, climbing, rising, or sitting (53%); hind-limb lameness (38%); tail paralysis (16%); and urinary or fecal incontinence (16%).
May/June 2008, Vol. 44
Neurological examination revealed pain on palpation or
hyperextension of the lumbosacral junction (91%) and conscious proprioceptive deficits (39%). The outcomes after
surgeries were again good, with excellent results reported
for 78% of dogs during follow-up (38±22 months).15
As with DLSS of dogs, diagnosis of cats with IVDD may
be difficult, and IVDD can be easily confused with chronic
orthopedic conditions. Clinical histories and physical findings for the cats in the authors’ study were similar to those
reported for dogs with DLSS. All cats in the authors’ study
were reluctant to jump, with low tail carriage seen in three
cats and reluctance to ambulate in two cats. All cats had
pain when the lumbosacral region was palpated, and all
(except the Manx) had pain on tail hyperextension.
Hansen’s type II disease predominated in this study, as it
does in dogs, and recoveries after dorsal decompressive
laminectomies were good to excellent in most cats. The
authors have not to date noted any recurrence of clinical
signs in the six cats that were treated for IVDD, which is
consistent with the other literature reports of IVDD in cats.
Recurrence has been documented in dogs.16
In contrast to dogs with DLSS reported in the literature,
the cats in the authors’ study were older, with a mean age of
12.6 years. No specific breed or sex predilection was noted.
One of the cats in this study had evidence of a Hansen’s type
I disk extrusion at the time of surgery, and one had urinary
retention. The persistent, postoperative urinary incontinence
in the Manx was probably associated with sacrocaudal dysgenesis, which is inherited in this breed as an autosomal
dominant trait with varying degrees of sacral or lumbar
deformities.17
Sacrocaudal dysgenesis and associated malformations
have been recognized in most breeds of cats and are especially common in tailless breeds. Many tailless cats do not
have neurological deficits, and sacral/caudal deformities are
usually reported as incidental radiographic findings.17
Clinical findings depend on the degree of cauda equina or
spinal cord malformation. Signs include paraparesis, paraplegia, megacolon, atonic bladder, absent anal reflex, urinary and fecal incontinence, and perineal analgesia.
Diagnosis is made based on clinical signs, radiography,
myelography, and CT scan. Bladder expressions and fecal
softeners can be used to manage mildly affected cases, but
recurrent urinary tract infections, megacolon, and chronic
constipation are common persistent problems. Treatment is
ineffective in severely affected cats.17
Three cats in the authors’ study had preexisting orthopedic disease:
1) The cat with concurrent cranial cruciate ligament rupture was obese and had cystic calculi. The stifle injury
was not addressed during follow-up, and this cat had
residual postoperative lameness.
2) The cat with medially luxating patellas had stabilization
of one patella performed during the same anesthetic/surgical episode as the dorsal decompressive
laminectomy. Clinical signs resolved completely, and
May/June 2008, Vol. 44
the contralateral patella was stabilized 6 weeks after the
first surgery.
3) The cat with a history of chronic renal failure and bilateral stifle degenerative joint disease (DJD) showed
improvement of lumbosacral clinical signs after surgery,
but urinary retention persisted. The DJD was not treated. Nine months after surgery, this cat died from renal
disease and congestive heart failure.
It is not known if the orthopedic disease was a factor in
the development of lumbosacral IVDD or if IVDD was a
sequela of orthopedic conditions in this patient population.
Limitations of this study include its retrospective nature
and the lack of consistent diagnostic imaging data for all
cases. Computed tomographic scans were performed in four
of the cases, but lumbosacral lesions can be difficult to visualize with CT. Magnetic resonance imaging may have
improved the authors’ diagnostic capabilities, but recent
research on DLSS in dogs suggests a high degree of agreement between CT and MRI.18 Therefore, the authors feel
that CT imaging was an acceptable diagnostic modality.
Furthermore, the recent canine study showed only a slight to
fair agreement between diagnostic imaging and surgical
findings.18
A further limitation of the study was the small sample
size. However, this is consistent with the low numbers of
feline IVDD cases that have been reported previously. All of
the cats in this study underwent surgical decompression;
therefore, no conservatively managed cases were available
for comparison.
Until recently, lumbosacral IVDD in cats has been infrequently recognized and reported, with only 30 reported
cases of feline IVDD.3,8,11,12 With one exception, all cases
in this series had long-standing clinical histories and clinical signs attributable to lumbosacral disease. Therefore, the
authors feel that the clinical signs correlated well with their
diagnostic and surgical findings. Furthermore, all cats had
clinical resolution or were significantly improved after lumbosacral decompression, regardless of concurrent disease
and advanced age.
Subtle signs such as reluctance to jump and low tail carriage may be overlooked as early indicators of IVDD in cats.
Therefore, the incidence of lumbosacral IVDD in cats may
be higher than previously recognized. Lumbosacral IVDD
should be considered as a differential diagnosis in all cats
having caudal lumbar pain or pain on tail hyperextension.
Conclusion
a Solu-Medrol; Pharmacia, Kalamazoo, MI 49001
Footnotes
11. King AS, Smith RN. Protrusion of the intervertebral disc in the cat.
Vet Record 1958;70:509-512.
12. King AS, Smith RN. Degeneration of the intervertebral disc in the
cat. Acta Orthop Scandinav 1964;34:139-158.
References
Lumbosacral IVDD in Six Cats
115
13. Rayward RM. Feline intervertebral disc disease: a review of the literature. Vet Comp Orthop Traumatol 2002;15:137-144.
14. Dhupa S, Glickman NW, Waters DJ. Functional outcome in dogs
after surgical treatment of caudal lumbar intervertebral disk herniation. J Am Anim Hosp Assoc 1999;35:323-331.
15. Oliver JE, Lorenz MD, Kornegay JN. Pelvic limb paresis, paralysis,
or ataxia. In: Handbook of Veterinary Neurology. 3rd ed.
Philadelphia: WB Saunders, 1997:129-172.
16. Bracken MB, Shepard MJ, Collins WF, et al. A randomized, controlled trial of methylprednisolone or naloxone in the treatment of
acute spinal-cord injury. Results of the Second National Acute Spinal
Cord Injury Study. N Engl J Med 1990;322:1405-1411.
17. Bagley RS, Tucker RL, Moore MP, et al. Intervertebral disk extrusion in a cat. Vet Radiol Ultrasound 1995;36:380-382.
18. McConnell JF, Garosi LS. Intramedullary intervertebral disk extrusion in a cat. Vet Radiol Ultrasound 2004;45:327-330.
19. Munana KR, Olby NJ, Sharp NJH, et al. Intervertebral disk disease
in 10 cats. J Am Anim Hosp Assoc 2001;37:384-389.
10. Knipe MF, Vernau KM, Hornof WJ, et al. Intervertebral disc extrusion in six cats. J Feline Med Surg 2001;3:161-168.
11. Lu D, Lamb CR, Wesselingh K, et al. Acute intervertebral disc
extrusion in a cat: clinical and MRI findings. J Feline Med Surg
2002;4:65-68.
12. Jaeger GH, Early PJ, Munana KR, et al. Lumbosacral disc disease in
a cat. Vet Comp Orthop Traumatol 2004;17:104-106.
13. Sjostrom L. Lumbosacral disorders. In: Slatter D, ed. Textbook of
Small Animal Surgery. 3rd ed. Philadelphia: WB Saunders,
2003:1227-1243.
14. Danielsson F, Sjostrom L. Surgical treatment of degenerative lumbosacral stenosis in dogs. Vet Surg 1999;28:91-98.
15. De Risio L, Sharp NJH, Olby NJ, et al. Predictors of outcome after
dorsal decompressive laminectomy for degenerative lumbosacral
stenosis in dogs: 69 cases (1987-1997). J Am Vet Med Assoc
2001;219:624-628.
16. Dhupa S, Glickman N, Waters DJ. Reoperative neurosurgery in dogs
with thoracolumbar disc disease. Vet Surg 1999;28:421-428
17. LeCouteur RA, Grandy JL. Diseases of the spinal cord. In: Ettinger
SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine. 5th
ed. Philadelphia: WB Saunders, 2000:645.
18. Suwankong N, Voorhout G, Hazewinkel HA, et al. Agreement
between computed tomography, magnetic resonance imaging, and
surgical findings in dogs with degenerative lumbosacral stenosis. J
Am Vet Med Assoc 2006;229:1924-1929.
Palliation of Clinical Signs in 48 Dogs
With Nasal Carcinomas Treated With
Coarse-fraction Radiation Therapy
Data from 48 dogs with nasal carcinomas treated with palliative radiation therapy (PRT) were
retrospectively reviewed. Factors potentially influencing resolution of clinical signs and survival after PRT were evaluated. Clinical signs completely resolved in 66% of dogs for a median of 120 days. The overall median survival time was 146 days. Duration of response to PRT
was shorter in dogs that had clinical signs for <90 days before PRT. Survival times were
shorter in dogs that had partial or no resolution of clinical signs after PRT than in dogs that
had complete resolution of clinical signs. J Am Anim Hosp Assoc 2008;44:116-123.
Tracy Gieger, DVM,
Diplomate ACVIM,
Diplomate ACVR
Kenneth Rassnick, DVM,
Diplomate ACVIM
Sheri Siegel, DVM,
Diplomate ACVR
David Proulx, DVM, MSpVM,
Diplomate ACVIM,
Diplomate ACVR
Philip Bergman, DVM, MS,
PhD, Diplomate ACVIM
Christine Anderson, DVM, MS,
Diplomate ACVIM,
Diplomate ACVR
Tracy LaDue, DVM,
Diplomate ACVIM,
Diplomate ACVR
Annette Smith, DVM, MS,
Diplomate ACVIM
Nicole Northrup, DVM,
Diplomate ACVIM
Royce Roberts, DVM,
Diplomate ACVR
Malignant neoplasms of the nasal cavity and paranasal sinuses cause local
soft-tissue and bony destruction, resulting in clinical signs such as epistaxis, sneezing, facial deformity, and upper-airway dyspnea.1-12 Without
therapy, progression is fairly rapid. The reported median survival times for
16 dogs with various intranasal neoplasms were 10.5 weeks from the initial onset of clinical signs and 3.5 weeks from presentation to a veterinary
facility.4 In a recent study of 139 dogs with untreated nasal carcinomas,
survival times ranged from 7 to 1114 days (median 95 days).12
Treatment options for dogs with nasal carcinoma include surgery,
external-beam radiation therapy (RT), brachytherapy, immunotherapy,
and chemotherapy.1-15 External-beam RT has become the treatment of
choice for nasal tumors, because historical evidence suggests that surgery
Introduction
From the Department of Clinical Sciences (Gieger, Rassnick), Cornell University
Hospital for Animals, CPC Box 31, Tower Road, Ithaca, New York 14853; New
England Veterinary Oncology Group (Siegel), 180 Bear Hill Road, Suite C,
Waltham, Massachusetts 02454; Veterinary Teaching Hospital (Proulx), College of
Veterinary Medicine, North Carolina State University, 4700 Hillsborough Street,
Raleigh, North Carolina 27606; The Animal Medical Center, Donaldson Atwood
Cancer Clinic, and Flaherty Comparative Oncology Laboratory (Bergman), 510
East 62nd Street, New York, New York 10021; Angell Memorial Animal Hospital
(Anderson), 350 South Huntington Avenue, Boston, Massachusetts 02130;
Southeast Veterinary Oncology (LaDue), 280 Corporate Way, Orange Park, Florida
32073; Small Animal Hospital (Smith), College of Veterinary Medicine, Auburn
University, Auburn, Alabama 36849; and the Departments of Small Animal
Medicine and Surgery (Northrup) and Anatomy and Radiology (Roberts), College
of Veterinary Medicine, The University of Georgia, 501 DW Brooks Drive, Athens,
Georgia 30602.
Doctor Gieger’s current address is California Veterinary Specialists, 2310 Faraday
Avenue, Carlsbad, California 92008.
RS
116
Doctor Proulx’s current address is Angel Care Cancer Center, 100 North Rancho
Santa Fe Road, Suite 133, San Marcos, California 92069.
JOURNAL of the American Animal Hospital Association
May/June 2008, Vol. 44
or chemotherapy alone rarely provides long-term tumor
control.1-11,14 Unfortunately, even with treatment, most
dogs with nasal carcinomas are eventually euthanized
because of local disease progression and worsening of clinical signs.
Nasal tumors are most often seen in older dogs (median
age approximately 10 years),3,6,7,11,13 and many affected
dogs have concurrent diseases that contribute to overall
morbidity. Concurrent illness also makes decisions about
treatment increasingly difficult for both the owner and the
veterinary oncologist. In some cases, advanced local disease
or the presence of metastasis makes the clinician hesitant to
recommend a definitive course of RT because of the potential for adverse effects in a dog with a poor long-term prognosis. For these dogs, a palliative course of RT may be
considered to minimize hospitalization, the number of anesthetic episodes, and adverse effects normally associated
with definitive RT.
The goal of palliative radiation therapy (PRT) is to
improve quality of life while minimizing treatment-associated morbidity. Radiation therapy can decrease pain associated
with bony lysis, inflammation, or tissue compression caused
by tumors. Improvement of clinical signs may also prolong
life, although this is not the primary goal of PRT.16-18
Information regarding use of PRT protocols in dogs with
sinonasal cancer is lacking. The purpose of the current study
was to evaluate the clinical characteristics and outcomes of
dogs with nasal carcinomas treated with PRT.
Materials and Methods
Criteria for Case Selection
Patient records from eight contributing institutions were
reviewed for the period between 1996 and 2005. Dogs that
had histologically confirmed nasal or paranasal carcinomas
treated with PRT were included in the study, as well as those
that had been treated with nonsteroidal antiinflammatory
drugs (NSAIDs), steroids, or antibiotics before or concurrently with PRT. Dogs that had inadequate follow-up or that
had received previous RT, chemotherapy, or surgery were
excluded.
Data abstracted from medical records included 1) patient
characteristics, such as age, weight, breed, presence of clinical signs, duration of clinical signs, and treatments before
diagnosis; 2) diagnostic information, such as results of
imaging methods and histopathological diagnosis; 3) treatment data, including reason for PRT, radiation source, dose
per fraction, number of fractions administered, schedule for
RT, and description of the radiation treatment field; and 4)
follow-up data, including adverse effects associated with
PRT, medications administered during and after completion
of PRT, response to PRT (including resolution of clinical
signs and response duration), survival time, and cause of
death. Follow-up information was obtained from existing
records or telephone interviews with the referring veterinarian and/or owner.
Case Data
Palliative Radiotherapy for Canine Nasal Tumors
117
Information was obtained, when available, on the results
of staging procedures, including cytological examination of
regional lymph nodes, radiography of the thorax and
abdomen, and ultrasonography of the abdomen. Systemic
staging was performed according to clinician preference.
Clinical tumor staging was based on results of computed
tomography (CT) or magnetic resonance imaging (MRI),
with tumors categorized according to a published classification system for sinonasal tumors.1 Clinical staging was not
assessed when CT or MRI findings were unavailable.
Duration of clinical signs before PRT was defined as the
interval between the onset of clinical signs (as reported in
the medical record) and the initiation of radiotherapy. For
dogs in which clinical signs resolved completely, response
duration was defined as the interval between the final dose
of PRT and recurrence of clinical signs. Dogs in which clinical signs did not resolve completely were not included in
analysis of response duration. Survival time was defined as
the time from the end of PRT until death from any cause.
Dogs that were free of clinical signs or alive at the last follow-up were included in analyses until the last day of follow-up, and then they were censored. Additionally, dogs
that received a second course of PRT were censored from
survival analyses at the time the second course was begun.
Risk factors were analyzed as possible predictors of
response to PRT or survival. These risk factors included
duration of clinical signs before the initiation of PRT (<90
days versus ≥90 days), Adams’ stage (stages 1 and 2 versus
stages 3 and 4), total radiation dose (<24 Gy versus ≥24
Gy), dose per fraction (<8 Gy versus ≥8 Gy), complete resolution of clinical signs during or after PRT (yes versus no),
and use of antiinflammatories (NSAIDs or steroids) with or
without antibiotics during and after PRT (yes versus no).
Chi-square and Fisher’s exact testsa were used to screen
categorical data for associations with complete resolution of
clinical signs. The Kaplan-Meier product-limit method was
used to estimate response duration and survival curves for
each potential risk factor. These curves were then compared
using the logrank test for censored data. Multivariable survival analysis using the Cox proportional-hazards method
was performed to evaluate the joint effects of potential risk
factors on response duration and survival. Variables with P
values ≤0.05 in the univariable analysis were initially considered in the multivariable analysis, with stepwise backward elimination used for final model selection. In the final
analysis, P values ≤0.05 were considered significant.
Statistical Analysis
Medical records of 65 dogs with nasal carcinomas were retrospectively evaluated for inclusion in the study. Ten dogs
that had inadequate follow-up were excluded, as were seven
dogs that had received chemotherapy concurrent with or
after PRT. Of the remaining 48 dogs, 23 were male (19 castrated) and 25 were female (24 spayed). Weights ranged
from 4 to 50 kg (median 24 kg, mean 24 kg). Age ranged
Results
118
JOURNAL of the American Animal Hospital Association
from 5 to 15 years (median 11 years, mean 11 years). Nine
dogs were mixed breeds, and 39 were purebreds (composed of
19 different breeds). The most common breeds were Labrador
retrievers (n=7), golden retrievers (n=6), and beagles (n=4).
The duration of clinical signs before evaluation was
known for 44 dogs and ranged from 7 to 730 days (median
90 days, mean 142 days). Clinical signs included epistaxis
(n=40, 83%), sneezing (n=31, 65%), nasal discharge (n=26,
54%), facial deformity (n=19, 40%), upper-airway dyspnea
(n=16, 33%), and ocular abnormalities (n=13, 27%). Most
dogs had more than one clinical sign at presentation. Ocular
abnormalities included decreased ocular retropulsion, third
eyelid protrusion, exophthalmos, and epiphora. One dog
with minimal signs related to the nasal cavity was presented
for evaluation of ataxia, acute-onset blindness, and seizures.
Of the 39 (81%) dogs treated empirically for nasal signs
before sinonasal neoplasia was diagnosed, 11 (28%) had
partial or complete resolution of signs after treatment. Dogs
were treated with NSAIDs (n=11), steroids (n=16), antibiotics (n=23), or combinations of these medications (n=10)
before PRT. In most cases, the resolution of clinical signs
resulting from these treatments lasted <1 month.
In 11 (23%) dogs, mandibular lymph nodes ipsilateral to
the tumor were aspirated. The records did not indicate
whether these lymph nodes were enlarged at diagnosis, but
no dogs had cytological evidence of lymph node metastasis.
Thoracic radiographs were taken in 47 (98%) dogs and were
unremarkable except for a presumed primary lung tumor seen
in one dog.
Information on tumor staging was available for 42 cases.
Stages were based on retrospective evaluation of CT (n=41)
or MRI (n=1) reports, and they were categorized as T1
(n=4), T2 (n=6), T3 (n=10), or T4 (n=22).1
May/June 2008, Vol. 44
The reasons for treating patients with PRT (as opposed to
definitive therapy) were documented in 40 (83%) cases. In
14 (35%) dogs, the extent of local disease was listed as the
cause for recommending PRT. In 24 (60%) cases, owners
requested PRT because of concerns about cost, potential for
toxicity, or travel/hospitalization associated with definitive
RT. In two (5%) dogs, PRT was recommended because of
concurrent diseases, including cardiac arrhythmias and the
presence of a presumed primary lung tumor.
Dogs were treated with a course of PRT using standard
protocols of each institution. After general anesthesia was
induced, dogs were treated with megavoltage radiation
using either a linear accelerator (n=32) or a Cobalt-60
teletherapy unit (n=16). Treatment planning was based on
CT/MRI scans (n=42) or on skull radiographs and anatomical landmarks (n=6). Computer-based treatment plans were
used for most cases in which advanced imaging was available. Dogs were treated with parallel opposed beams
(n=43), single dorsal beams (n=4), or three or more orthogonal beams (n=1). Blocks and wedges were used at the discretion of the radiation therapist but were not used in most
cases. Ipsilateral mandibular lymph nodes were not irradiated in any dogs. The total radiation dose ranged from 16 to
40 Gy (median 24 Gy). Dose per fraction ranged from 4 to
10 Gy (median 8 Gy) [see Table]. Oral medications (including steroids, NSAIDs, and/or antibiotics) to help control
clinical signs related to the nasal tumor or other conditions
(e.g., osteoarthritis) were administered to 16 dogs during
and/or after completion of PRT.
In 47 (98%) of the 48 dogs, the planned course of treatment
was completed. The dog in which the course of therapy was
not completed was euthanized after two of the three planned
treatments, because the owner perceived a lack of response.
Table
Dosing Schemes for 48 Dogs With Nasal Carcinomas Treated With Coarse-fractionated
Palliative Radiation Therapy
Treatment Day
Dose Per Fraction (Gy)
Total Dose (Gy)
No. of Dogs
0-7-21
8
24
23
0-7-21
10
30
2
0-7-14
8
24
7
0-7-14-21
5
20
1
0-7-14-21
6
24
4
0-7-14-21
8
32
3
0-7-14-21-28
8
40
2
0-1-2-3-4
4
20
5
0-7
8
16
1
May/June 2008, Vol. 44
In 39 (81%) dogs, at least one eye was irradiated. In 11
(28%) of these 39 dogs, ocular medications (including eye
lubricants, topical cyclosporine, or antibiotic ointments)
were prescribed during and/or after completion of PRT.
Because of the retrospective nature of this study, grading
the adverse effects of RT using standardized schemes was
not possible.19 Information on adverse effects during or
after completion of PRT was available for 40 dogs, and
acute adverse effects were reported in 14 (35%) dogs. Acute
toxicities were generally mild and included (listed in order
of decreasing frequency) oral mucositis, conjunctivitis, pitting edema in the irradiated field, dermatitis, and uveitis.
Many dogs had multiple concurrent adverse effects.
Asymptomatic alopecia, leukotrichia, and hyperpigmentation of the skin in the irradiated field were common in dogs
that survived >3 months after PRT.
The incidence of acute ocular toxicity was difficult to
discern, because some dogs were treated prophylactically
with eye lubricants and topical ocular medications (e.g.,
antiinflammatory or antibiotic ointments/drops) during PRT
and for 2 to 4 weeks after. Chronic ocular toxicities (i.e.,
conditions necessitating medications for >4 weeks after
PRT) were reported in five (13%) of the 39 dogs that had at
least one eye irradiated. Chronic toxicities included conjunctivitis, corneal ulceration or perforation, loss of vision,
keratoconjunctivitis sicca, severe mucoid ocular discharge,
cataract formation, blepharospasm, and uveitis. Most dogs
that experienced chronic ocular toxicity had multiple concurrent ocular side effects.
One dog developed lymphadenomegaly, cytological evidence of mandibular lymph node metastasis, and recurrence
of nasal signs 256 days after completion of the initial course
of PRT. This dog was treated with a second course of PRT, in
which both the nasal cavity and lymph node were irradiated.
Two dogs developed evidence of systemic metastasis
after PRT. One of these had been treated for a stage T11
nasal adenocarcinoma and developed coughing and exercise
intolerance 70 days after PRT. Thoracic radiographs
revealed a multifocal nodular pattern consistent with metastasis, but this was not confirmed cytologically or histologically. The other dog, which had been treated for a stage T31
nasal adenocarcinoma, developed recurrence of nasal signs
and cytological evidence of metastatic carcinoma to the
liver, spleen, ribs, and scapulae 390 days after PRT.
Seizures were reported in four dogs 80 to 240 days
(median 135 days) after PRT. Only one of these dogs had a
history of seizure activity before PRT. Three of these dogs
had been treated for stage T41 tumors (including brain invasion), and one had a stage T31 tumor. After the onset of
seizures in one dog, a repeat CT scan confirmed progressive
brain invasion by the tumor.
Response to PRT was evaluated in all dogs based on a
retrospective review of medical records. In 32 (66%) of
the 48 cases, clinical signs had completely resolved by the
end of PRT or soon after. The remaining 16 dogs had only
partial (n=12) or no (n=4) response to therapy. Dogs with
partial or no response were combined in the data analysis.
Palliative Radiotherapy for Canine Nasal Tumors
119
No association was found between resolution of clinical
signs and any of the analyzed risk factors. Thirty dogs experienced complete resolution of clinical signs but subsequently relapsed, while two remained free of clinical signs
113 and 883 days after PRT. Analysis of censored survival
curves suggested a median response duration of 120 days
(mean 209 days, range 20 to 1238 days [Figure 1]). One
year after treatment, 10% of dogs were free of clinical signs;
2 years after treatment, 6% were free of clinical signs.
The only risk factor significantly associated with shorter
response duration was the duration of signs before diagno-
Figure 1—Response duration for 32 of 48 dogs with nasal
tumors in which clinical signs resolved completely after palliative radiation therapy. The overall median response duration was 120 days (95% confidence interval [CI] was 93 to
146 days). Vertical markers represent censored data.
sis. Dogs that had <90 days of nasal signs before diagnosis
were 4.1 times more likely to have a relapse (95% confidence interval [CI] 1.6 to 10.6, P=0.004). In these nine
dogs, the median response duration was 80 days, versus 150
days in dogs that had ≥90 days of clinical signs before diagnosis (n=20, P=0.001) [Figure 2].
During the follow-up period, 36 dogs died. Twelve dogs
were censored from survival analysis; three were alive 691,
783, and 883 days after PRT, and nine were censored at the
time of repeat irradiation. Analysis of censored survival
curves indicated that the overall median survival time was
146 days (mean 284 days, range 0 to 1238 days) [Figure 3].
One year after treatment, 25% of dogs were alive; 2 years
after treatment, 9% were alive.
Risk factors significantly associated with shorter survival
during univariate analysis were duration of clinical signs for
<90 days before diagnosis (P=0.044) and lack of resolution
of clinical signs after PRT (P<0.0001). In multivariate analysis, only “complete resolution of clinical signs” remained
significant. Dogs that did not have complete resolution of
clinical signs after PRT were three times more likely to die
(95% CI 1.4 to 6.5, P=0.006) than dogs in which clinical
120
JOURNAL of the American Animal Hospital Association
Figure 2—The median response duration was 80 days
(95% CI 51 to 109 days) (dashed line) for nine dogs with
nasal carcinomas and clinical signs for <90 days before
diagnosis, versus 150 days (95% CI 115 to 185 days) for
20 dogs with clinical signs present for ≥90 days before
diagnosis (solid line) (P=0.001).
May/June 2008, Vol. 44
Figure 4—The median survival time was 42 days (95% CI
3 to 81 days) (dashed line) for 16 dogs in which clinical
signs did not resolve, versus 255 days (95% CI 29 to 481
days) for 32 dogs in which clinical signs resolved completely after palliative radiation therapy (solid line)
(P<0.0001).
received two additional 8-Gy doses 1 week apart at an
unknown interval after the first treatment. Nine (82%) of 11
dogs had a complete response to the second course of
PRT. Duration of response varied, but it was >100 days in
seven dogs.
Definitive treatment for canine nasal tumors using externalbeam RT consists of total radiation doses of 36 to 57 Gy
divided into 10 to 19 fractions. Survival times after definitive RT range from 7 to 23 months, with 1-year survival
rates of 37% to 60% and 2-year survival rates of 17% to
48%.1,3-11 Factors associated with longer survival include
low stage,1,3 age <10 years,11 lack of metastasis to regional
lymph nodes or lungs,7 lack of facial deformity, and complete resolution of clinical signs.6 In the present study, the
overall median survival time was 146 days, with 25% of
dogs alive at 1 year and 9% alive at 2 years after PRT. The
shorter survival times for the dogs in the current study may
be related to 1) more advanced-stage nasal disease than in
previous studies; 2) a lower total radiation dose (i.e., median of 24 Gy in this study) compared to previous studies; 3)
a fractionation schedule that could favor tumor repopulation
(i.e., once-weekly treatments); and 4) a higher prevalence of
dogs with concurrent illness compared to that reported in
previous studies.
The shorter survival time in the authors’ study may have
also been related to owner-specific factors. In this study,
60% of dogs were treated with PRT (instead of a definitive
course of RT) at the owners’ request; many of these owners
were specifically seeking therapies unlikely to result in
adverse effects. Possibly, the owners of these dogs had less
tolerance for the morbidity associated with treatment and/or
lack of response to treatment, and they may have elected
euthanasia sooner than owners of dogs in other studies.
Discussion
Figure 3—Overall survival time for 48 dogs treated with
palliative radiation therapy for sinonasal carcinomas. The
median survival time was 146 days (95% CI 114 to 178
days).
signs resolved completely. The median survival time for
dogs that did not have complete resolution of clinical signs
(n=16) was 42 days, versus 255 days for dogs in which clinical signs resolved completely after treatment (n=32,
P<0.0001) [Figure 4].
Eleven (23%) dogs that completely responded to the first
course of PRT were treated with a second course of PRT
when clinical signs recurred. The second course of PRT was
initiated 70 to 573 days (median 171 days; mean 215 days)
after the first course was completed. Dosing schedules were
the same as the first course of PRT for 13 of 15 dogs. One
of the remaining dogs received two additional 8-Gy doses at
6 and 22 months after the first treatment, and the other
May/June 2008, Vol. 44
The only factor significantly associated with survival
time in this study was resolution of signs after PRT. The
median survival time for dogs that did not have complete
resolution of clinical signs was 42 days, versus 255 days for
dogs that had complete resolution of signs after treatment.
This finding is comparable to that of a 2001 study of dogs
treated with orthovoltage RT, in which dogs with resolution
of signs after RT had a median survival time of 476 days,
versus 133 days for dogs with continued clinical signs.6
Few published studies of RT for canine nasal tumors
address either the likelihood of response to treatment or the
response duration, because at least some nasal signs persist
long term in many dogs after treatment. Only one study
addressed this issue objectively; in that study, 24 dogs were
treated with Cobalt radiation for nasal carcinomas, and CT
scans were performed at 1, 3, 6, and 12 months after treatment. The duration of local control was longer in the 11
dogs with marked tumor regression on CT (389 days) than
in dogs without tumor regression (161 days).20 Other factors associated with longer response include surgical excision of the tumor before RT4 and low tumor stage.1,3
In the authors’ study, the complete response rate to PRT
was 66%, with an overall response duration of 120 days.
Response duration was assessed through careful examination of medical records and discussion with owners and
referring veterinarians. However, it is possible that response
rates were over- or underestimated because of the retrospective nature of the study.
The only factor significantly associated with longer
response was “duration of clinical signs for ≥90 days before
diagnosis.” It is likely that such tumors grew slowly, making them more responsive to PRT because of adequate oxygenation and a lack of tumor cell repopulation between
fractions.21 Conversely, tumors resulting in a rapid onset of
clinical signs may have been less sensitive to radiation
because of hypoxic areas within the tumor (related to rapid
growth) that allowed continued tumor growth and shorter
symptom-free interval.
To date, only two other studies have evaluated treatment
responses in dogs with nasal cancer after PRT or coarse
radiation-fractionation schemes.2,4 In a retrospective study
of 56 dogs with various histological types of sinonasal neoplasia, PRT was administered with a linear accelerator in
four weekly 9-Gy fractions.2 Treatment plans and tumor
stage determination were based solely on skull radiographs.
Clinical signs improved by the end of PRT in 95% of these
dogs, but most (89%) dogs were eventually euthanized as a
result of their tumors. The median survival time from the
last day of PRT was 212 days (range 38 to 386 days), with
a 1-year survival rate of 45% and a 2-year survival rate of
15%.2 There was no difference in survival between dogs
that had carcinomas versus sarcomas or between stages of
disease. In another report, 12 dogs with a variety of tumor
types that were staged using skull radiographs were treated
with PRT administered in four weekly, 9-Gy fractions.4 In
these dogs, the median survival time was 441 days (range
301 to 1400 days), with 58% alive 1 year after PRT and 13%
Palliative Radiotherapy for Canine Nasal Tumors
121
alive 2 years after PRT. No difference was seen in survival
of dogs with different tumor types. In these reports (as in the
present study), toxicities were mild, with most dogs
responding to therapy. The longer median survival times
and 1- and 2-year survival rates reported in these earlier
studies may be because a larger portion of dogs had less
advanced tumors than dogs in the present study. However,
direct comparisons are difficult, because tumors in earlier
studies were staged using skull radiographs rather than
cross-sectional imaging.
The primary goal of PRT is to alleviate discomfort, not
necessarily to prolong survival.22-24 Therefore, assessing
outcomes after PRT is difficult, especially in veterinary
patients. Patient response to PRT should ideally be measured both qualitatively and quantitatively. In people,
response is assessed via questionnaires regarding mobility,
pain, analgesic use, and overall improvement before, during, and after treatment.22-24 In one published study of PRT
in dogs with various advanced-stage malignancies, 24 dogs
were treated with 8-Gy fractions on days 0, 7, and 21—for
a total dose of 24 Gy.16 Owners were asked to complete
questionnaires that assessed the appetite, activity level, and
lameness of their dog. Analgesic requirements, weight of
the dog, and tumor response were also recorded before, during, and after therapy. Twenty (87%) of 23 dogs experienced partial or complete pain relief, and most owners felt
that their pet had an improved quality of life and that they
would consider the same treatment for another pet.16
Unfortunately, this type of information can rarely be
obtained when reviewing records in a retrospective manner.
Prospective studies using detailed questionnaires
addressing owner and clinician perceptions of patient status
would improve the authors’ knowledge about responses to
RT. Quantitative measurements of response should include
measurement of the primary and metastatic tumor and evaluation of disease-free interval and survival time. Although
the goal of PRT is not necessarily to prolong survival,
improved quality of life may lead to longer survival. Many
animals undergoing PRT might otherwise be euthanized
because of the severity of their clinical signs. Hopefully,
evaluation of both response duration and overall survival
time gives a reasonable estimate for meaningful (i.e., good
quality of life) survival. In the authors’ study, survival time
was significantly affected only by response to therapy. Dogs
that did not have a response to PRT were likely euthanized
because of continued clinical signs and disease progression.
Palliative RT uses less intense dosing schedules and a
lower total radiation dose than definitive RT, resulting in
fewer acute adverse effects.16-18 In the present study, 35%
of dogs had acute RT toxicity, which was generally mild and
resolved with supportive care. This toxicity rate is lower
than that reported for canine patients treated with definitive
RT for nasal tumors, although differences in toxicity grading and follow-up make it somewhat difficult to compare
results of this study to those of definitive RT studies.
Retrospective studies permit only limited assessment of
toxicity. Ideally, prospective evaluations during treatment
122
JOURNAL of the American Animal Hospital Association
could be documented using a published toxicity scheme.19
Both acute and chronic toxicities possibly are underestimated in this study because of inconsistent follow-up and
incomplete medical records.
The reported occurrence of acute ocular, cutaneous, and
oral adverse effects in dogs treated with definitive RT protocols is 67% to 95%, 92%, and 81% to 95%, respectively.1,6,9 Chronic ocular toxicity was seen in 13% of the dogs
in the present study, which is lower than the 39% to 76%
reported after definitive RT for nasal tumors;1,3,6,9,11,25 but
concern is still warranted given the increased morbidity and
cost associated with ocular toxicity from PRT.
The ideal fractionation scheme for PRT has yet to be
determined. Studies have not consistently revealed a doseresponse relationship in people treated with coarse-fractionation schemes for metastatic bone cancer.22-24 Few
veterinary studies have examined the effect of fractionation
on outcome in palliative protocols, and in the present study
no significant differences were seen in outcomes for dogs
treated with different total doses or doses per fraction. Most
published fractionation schemes for PRT in dogs are similar
to those reported here and involve weekly treatments for 2
to 4 weeks using 8 to 10 Gy per treatment—for a total dose
of 16 to 30 Gy.16,26-28 The advantages of a once-weekly
treatment schedule include a decreased number of anesthetic episodes and decreased incidence of acute adverse effects
(compared with daily therapy), because normal tissues have
time to repair between treatments.
The disadvantages of a weekly protocol include the possibility of repopulation and repair of tumor cells and an
increased chance of late-occurring adverse effects in susceptible tissues (e.g., muscle, nerve, and bone) as the dose
per fraction is increased.21,29 Late adverse effects may
include fibrosis and necrosis of tissues and (rarely) secondary tumor formation at the irradiated site.29 These effects
are usually not seen until ≥1 year after radiation and are
therefore uncommon in treated animals, which often do not
survive this long after a course of PRT.
The occurrence of late side effects can be minimized by
decreasing the fraction size.29 As an example, one of the
treatment protocols in this study used five consecutive,
daily 4-Gy fractions. Daily treatments allow little time for
tumor cells to repair and repopulate, which may result in
improved response. The lower dose per fraction (compared
with most palliative protocols that use 8 to 10 Gy per fraction) decreases the chance of late side effects.29 In addition,
the lower total dose (20 Gy) in this protocol may allow normal tissues to tolerate re-treatment if clinical signs recur.
Clinicians might otherwise be hesitant to recommend retreatment after protocols using higher total doses of radiation. Further studies to determine the ideal dosing scheme
for PRT in dogs are indicated.
Eleven (23%) of the dogs in this study received a second
course of PRT. All these dogs completely responded to the
first course of PRT and were re-treated after relapse of clinical
signs. Controlled studies on repeated irradiation are lacking in
the veterinary literature. In one study, 51 dogs and cats with
May/June 2008, Vol. 44
various tumors were given a second course of RT after an initial definitive course. A total of 86% had partial or complete
response at 2 months after the second course of RT, and 41%
were alive 1 year later.30 Complications after reirradiation
have not been documented in the present study, although most
dogs are deceased.
Clinicians and owners of dogs with nasal cancer may seek
either alternatives to RT or synergistic therapies that may
enhance quality of life and prolong survival compared with
RT alone. Options include chemotherapy, pain medications,
steroids, NSAIDs, and surgery. Chemotherapy has shown
some potential for treatment of primary and metastatic sinonasal cancer, although large prospective studies have
yet to be performed.14,31 Cyclo-oxygenase-2 (COX-2)
inhibitors may alleviate pain and clinical signs, may have
antineoplastic properties, and may act as radiation sensitizers.31-33 In a recent study of dogs with nasal cancer, survival
times were longer for dogs treated with definitive RT followed by nasal cavity exenteration than for dogs treated
with RT alone, although the surgical group had substantial
postoperative morbidity.34 In addition to these adjunct therapies, improvements in RT treatment planning and delivery
(such as 3D conformal RT and intensity-modulated RT) are
increasingly available in veterinary medicine.35 The goals
of these therapies are to improve dose distribution throughout the tumor volume and to decrease adverse effects in
adjacent normal structures.
The goal of PRT is to improve the patient’s quality of life
while minimizing treatment-associated morbidity. In most
dogs of this study, clinical signs resolved completely and
usually with only mild signs of toxicity. The symptom-free
intervals and overall survival times for nasal cancer cases
treated with PRT are shorter than those in published results
for definitive RT. Palliative RT should be considered as a
treatment option in dogs with advanced local, metastatic, or
severe concurrent disease that precludes definitive therapy.
Hopefully the ongoing study of canine nasal cancer will
result in decreased side effects, improved patient comfort,
and prolonged survival.
Conclusion
a SPSS 10; Statistical Analytical Software, Chicago, IL
Footnotes
11. Adams WM, Miller PE, Vail DM, et al. An accelerated technique for
irradiation of malignant canine nasal and paranasal sinus tumors. Vet
Radiol Ultrasound 1998;39:475-481.
12. Mellanby RJ, Stevenson RK, Herrtage ME, et al. Long-term outcome of 56 dogs with nasal tumours treated with four doses of radiation at intervals of seven days. Vet Rec 2002;151:235-257.
13. Théon AP, Madewell BR, Harb MF, et al. Megavoltage irradiation of
neoplasms of the nasal and paranasal cavities in 77 dogs. J Am Vet
Med Assoc 1993;202:1469-1475.
14. Morris RS, Dunn KJ, Dobson JM, et al. Effects of radiotherapy
alone and surgery and radiotherapy on survival in dogs with nasal
tumors. J Sm Anim Pract 1994;35:567-573.
15. Adams WM, Withrow SJ, Walshaw R, et al. Radiotherapy of malignant nasal tumors in 67 dogs. J Vet Am Med Assoc 1987;191:
311-315.
References
May/June 2008, Vol. 44
16. Northrup NC, Etue SM, Ruslander DM, et al. Retrospective study of
orthovoltage radiation therapy for nasal tumors in 42 dogs. J Vet
Intern Med 2001;15:183-189.
17. Henry CJ, Brewer WG, Tyler JW, et al. Survival in dogs with nasal
adenocarcinoma: 64 cases. J Vet Intern Med 1998;12:436-439.
18. Thrall DE, Harvey CE. Radiotherapy of malignant nasal tumors in
21 dogs. J Am Vet Med Assoc 1983;183:663-666.
19. McEntee MC, Page RL, Heidner GL, et al. A retrospective study of
27 dogs with intranasal neoplasms treated with cobalt radiation. Vet
Radiol 1992;32:135-139.
10. Evans SM, Goldschmidt M, McKee LJ, et al. Prognostic factors and
survival after radiotherapy for intranasal neoplasms in dogs. J Am
Vet Med Assoc 1989;194:1460-1463.
11. LaDue TA, Dodge R, Page RL, et al. Factors influencing survival
after radiotherapy of nasal tumors in 130 dogs. Vet Radiol
Ultrasound 1999;40:312-317.
12. Rassnick KM, Goldkamp C, Erb H, et al. Evaluation of factors associated with survival in dogs with untreated nasal carcinomas: 139
cases (1993-2003). J Am Vet Med Assoc 2006;229(3):401-406.
13. Patnaik AK. Canine sinonasal neoplasms: clinicopathological study
of 285 cases. J Am Anim Hosp Assoc 1989;25:103-114.
14. Hahn KA, Knapp DW, Richardson RC, et al. Clinical response of
nasal adenocarcinoma to cisplatin chemotherapy in 11 dogs. J Am
Vet Med Assoc 1992;200:355-357.
15. Thompson JP, Ackerman N, Bellah J, et al. Iridium brachytherapy,
using an intracavitary afterload device, for treatment of intranasal
neoplasms in dogs. Am J Vet Res 1992;53:617-622.
16. Bateman KE, Catton PA, Pennock PW, et al. 0-7-21 radiation therapy for the palliation of advanced cancer in dogs. J Vet Intern Med
1994;8:394-399.
17. Siegel S, Kronin KL. Palliative radiotherapy. Vet Clin N Am Sm
Anim Pract 1997;1:149-155.
18. Thrall DE, LaRue SM. Palliative radiation therapy. Semin Vet Med
Surg (Small Anim) 1995;10(3):205-208.
19. LaDue T, Klein MK. Toxicity criteria of the veterinary radiation
oncology group. Vet Radiol Ultrasound 2001;42:475-476.
20. Thrall DE, Heidner GL, Novotney CA, et al. Failure patterns following cobalt irradiation in dogs with nasal carcinoma. Vet Radiol
Ultrasound 1993;34:126-133.
21. Hill RP, Bristow RG. The scientific basis of radiotherapy. In:
Tannock IF, Hill RP, Bristow RG, Harrington L, eds. The Basic
Science of Oncology. 4th ed. New York: McGraw Hill, 2005:
311-314.
22. Bone Pain Trial Working Party. 8 Gy single fraction radiotherapy for
the treatment of metastatic skeletal pain: randomized comparison
with a multifraction schedule over 12 months of patient follow-up.
Radiother Oncol 1999;52:111-121.
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23. Hoskin PJ, Price P, Easton D, et al. A prospective randomized trial of
4 Gy or 8 Gy single doses in the treatment of metastatic bone pain.
Radiother Oncol 1992;23:74-78.
24. Arcangeli GA, Giovinazzo G, Saracino B, et al. Radiation therapy in
the management of symptomatic bone metastasis: the effect of total
dose and histology on pain relief and response duration. Int J Rad
Biol Phys 1998;42:1119-1126.
25. Roberts SM, Lavach JD, Severin GA, et al. Ophthalmic complications following megavoltage irradiation of the nasal and paranasal
cavities in dogs. J Am Vet Med Assoc 1987;190:43-47.
26. Green EM, Adams WM, Forrest LJ. Four fraction palliative radiotherapy for osteosarcoma in 24 dogs. J Am Anim Hosp Assoc
2002;38:445-451.
27. Ramirez O, Dodge RK, Page RL, et al. Palliative radiotherapy of
appendicular osteosarcoma in 95 dogs. Vet Radiol Ultrasound
1999;4:517-522.
28. McEntee MC, Page RL, Novotney CA, et al. Palliative radiotherapy
for canine appendicular osteosarcoma. Vet Radiol Ultrasound
1993;34:367-370.
29. Wong CS, Hill RP. Experimental radiotherapy. In: Tannock IF, Hill
RP, eds. The Basic Science of Oncology. 3rd ed. New York:
McGraw-Hill, 1998:326-346.
30. Turrel JM, Théon AP. Reirradiation of tumors in dogs and cats. J Am
Vet Med Assoc 1988;193:465-469.
31. Langova V, Mutsears AJ, Phillips B, et al. Treatment of eight dogs
with nasal tumors with alternating doses of doxorubicin and carboplatin in conjunction with oral piroxicam. Aust Vet J 2004;82:
676-680.
32. Kleiter M, Malarkey DE, Ruslander DE, et al. Expression of
cyclooxygenase-2 in canine epithelial nasal tumors. Vet Radiol
Ultrasound 2004;45:255-260.
33. Borazacchiello G, Paciello O, Papparella S. Expression of cyclooxygenase-1 and -2 in canine nasal carcinomas. J Comp Path
2004;131:70-76.
34. Adams WM, Bjorling DE, McAnulty JF, et al. Outcome of accelerated radiotherapy alone or accelerated radiotherapy followed by exenteration of the nasal cavity in dogs with intranasal neoplasia: 53
cases (1990-2002). J Am Vet Med Assoc 2005;227:936-941.
35. McEntee MC. Veterinary radiation therapy: review and current state
of the art. J Am Anim Hosp Assoc 2006;42:94-109.
Feline Chondrosarcoma: A Retrospective
Study of 67 Cats (1987-2005)
The histories of 67 cats diagnosed with chondrosarcoma (CSA) from 1987 to 2005 were
reviewed. The mean age was 9.6 years, and males were 1.9 times more likely to be affected
than females. Chondrosarcomas were diagnosed in the following sites: appendicular and
axial skeleton, nasal cavity, facial bones, and extraskeletal sites. Of the 46 (70%) CSA associated with bone, 63% arose in long bones and 37% arose in flat bones. The remaining (30%)
CSA arose in the subcutis. In cases available for follow-up (n=24), no definitive evidence of
metastases was found. Cats that underwent radical surgical therapies were more likely to
achieve long-term control or cure. J Am Anim Hosp Assoc 2008;44:124-130.
Amy C. Durham, MS, VMD
Catherine A. Popovitch, DVM,
Diplomate ACVS,
Diplomate ECVS
Michael H. Goldschmidt, MSc,
BVMS, MRCVS,
Diplomate ACVP
RS
From the Laboratory of Pathology and
Toxicology (Durham, Goldschmidt),
School of Veterinary Medicine,
University of Pennsylvania,
3800 Spruce Street,
Philadelphia, Pennsylvania 19104
and Veterinary Specialty and
Emergency Center (Popovitch),
1900 West Old Lincoln Highway,
Langehorne, Pennsylvania 19047.
124
Chondrosarcoma (CSA) is a malignant tumor in which the neoplastic
cells produce chondroid and varying amounts of fibrillar matrix, but
never osteoid.1 Feline CSA appears to grow slowly and invade locally,
but it rarely metastasizes. Survival time seems to be lengthened by
aggressive surgeries such as amputation, and information on therapies
such as radiation is limited.2,3 The purposes of this study are to detail the
signalment and tumor location in 67 cats diagnosed with CSA and to
summarize the treatment methods for the 24 cats that were available for
follow-up.
The characteristics and biological behavior of CSA in cats are not well
defined. In one survey, only two of 256 neoplasms in cats were CSA.4
Feline CSA has been reported in studies of primary bone tumors, nonlymphoma tumors of the vertebral canal, and nasal tumors; also, several
case reports have described CSA in cats, including two reports of CSA
arising in multilobular chondromas.2,3,5-10 In one study of primary bone
tumors in 24 cats, osteosarcoma (OSA) was the most common, followed
by juxtacortical OSA and CSA.5 The CSAs reported in this study arose
from the mandible, proximal tibia, and scapula. A subsequent study of primary bone tumors in cats indicates that CSA is as common as OSA, with
tumors arising from the femur, ischium, metacarpal bones, and scapula.2
Chondrosarcomas also comprise a subset of sarcomas that arise in soft
tissues. In a study of 23 cats with “soft-tissue sarcomas,” two cases were
classified as CSA.11 In another study by Hendrick and Brooks, the histology and immunohistochemistry of sarcomas arising in vaccination
sites were examined.12 Only one (2%) of the 46 postvaccinal sarcomas
was a CSA; most of these sarcomas were fibrosarcomas and malignant
fibrous histiocytomas. A similar incidence (2%) of CSA in vaccine-associated sarcomas was found in another immunohistochemical study.13
In contrast to CSA in cats, CSA in dogs is fairly well characterized. It
accounts for approximately 10% of primary bone tumors in dogs and is,
therefore, second only to OSA in incidence of primary bone tumors.14,15
In dogs, 61% of CSAs originate in flat bones; in one study, 50% of CSAs
arose in the nasal cavity.16,17 Local recurrence, not metastasis, is the primary cause of treatment failure in dogs.16
Introduction
JOURNAL of the American Animal Hospital Association
May/June 2008, Vol. 44
Feline Chondrosarcoma
Surgical pathology reports dating between 1987 and 2005
were obtained for all cats diagnosed with CSA by the
Laboratory of Pathology and Toxicology at the University
of Pennsylvania School of Veterinary Medicine. Tissues
were fixed in 10% buffered formalin, embedded in paraplast, cut, and stained with hematoxylin and eosin.
Histopathology slides of all 67 cases were reviewed by one
veterinary pathologist to confirm CSA. Chondrosarcomas
are composed of interwoven bundles, sheets, and nests of
cells within a lightly basophilic, chondroid matrix. Cells
have a moderate amount of amphophilic cytoplasm, indistinct borders, and large ovoid nuclei. Cellular and nuclear
pleomorphism, binucleation, and frequent mitoses are common features. Tumor cells may produce neoplastic chondroid, fibrillar matrix, and bone formed by endochondral
ossification of tumor cartilage [see Figure]. Cats with
tumors producing varying amounts of both tumor chondroid
and tumor osteoid were excluded from the study.
Information about age, sex, breed, and tumor location
was obtained from the biopsy reports. Tumors were classified as arising from the nasal cavity, appendicular skeleton
(i.e., humerus, radius/ulna, carpus, femur, tibia, tarsus, digit),
Materials and Methods
A
125
axial skeleton (i.e., scapula, sternum, rib, vertebra, pelvis),
facial bones (i.e., skull, maxilla, mandible), and extraskeletal
regions (i.e., subcutaneous tissues, subcutis). Bone tumors
were also categorized as those involving bones that develop
via endochondral ossification (long bones) or those involving bones that develop from intramembranous ossification
(flat bones). Tumors within the subcutis were further categorized as originating from the axilla, interscapular region, thoracic region, flank, hind limb, or lumbar area.
Additional information was obtained for all cases from
the form submitted by the referring veterinarian that
accompanies every biopsy sample. Information obtained
from this form included species, breed, sex, birth date, case
history, gross appearance of the tumor, number of lesions,
size, duration and rate of growth, treatment, and location. A
section of the form was available to indicate the type of
sample submitted (e.g., wedge, entire specimen, Tru-Cut,
punch, fragment, endoscopic, or other), and yes/no questions were provided to indicate lymph node involvement,
tumor encapsulation, and excisional biopsy. Follow-up
information was obtained from hospital records and questionnaires that were sent to the referring veterinarians.
Additional clinical data (i.e., current status, survival time,
C
Figure—Neoplastic cells are arranged in nests and sheets
and surrounded by lightly basophilic, chondroid matrix.
Note marked nuclear and cellular pleomorphism and binucleate cells. Neoplastic cells have moderate amounts of
finely vacuolated, amphophilic cytoplasm; large, oval, finely
stippled nuclei; and prominent nucleoli. Mitoses are often
variable. (Hematoxylin and eosin stain, A 10×; B 20×;
C 40×.)
B
126
JOURNAL of the American Animal Hospital Association
radiographs, blood work, clinical signs, and treatment)
were available for 24 cats. For the purposes of this study,
treatment options included incisional and excisional biopsies, radical surgery (e.g., amputation), or chemotherapy
and/or radiation therapy. Notation was made if the tumor
was located in a previous vaccination site.
To assess differences in age, breed, and sex, cats with
CSA were compared to the general population of cats with
surgical accessions during the same time period. Categorical
data were compared using either the chi-square or Fisher’s
exact test, and Student’s t-test was used for continuous data.
Analysis of variance was used to examine tumor location
with regard to age. The chi-square test was used to examine
tumor location with regard to sex. The Kaplan-Meier product limit method was used to determine the median survival
time for cats with CSA. When applicable, data are presented
as odds ratios (ORs) with 95% confidence limits (CIs). All
analyses were performed using SAS statistical software.a A
P value <0.05 was considered statistically significant.
May/June 2008, Vol. 44
were composed of bundles, nests, and sheets of neoplastic
chondrocytes; some contained areas of necrosis, endochondral ossification, or mineralization. Aggressive histological
features included severe pleomorphism, bi- or trinucleation,
and numerous mitotic figures (approximately two to four
per high-power field).
Forty-six (70%) of the tumors were associated with bone.
Thirteen (28%) tumors arose from the axial skeleton and
included the following sites: scapula (15%), vertebra
(6.5%), pelvis (2.2%), and sternum (4.3%). Appendicular
CSAs accounted for 52% (n=24), and sites included the
humerus (6.5%), radius/ulna (4.3%), femur (13%), tibia
(8.7%), carpus (4.3%), tarsus (2.2%), and digits (13%). Six
(13%) CSAs arose from facial bones, including the skull
bones (4.3%) and mandibular/maxillary bones (8.7%).
Three (6.5%) CSAs arose from the nasal cavity [Table 1].
Tumor Location
Results
Age Distribution
The mean age of affected cats (n=67) was 9.6 years, and the
median age was 9 years (range 2 to 18 years). No significant
difference was found in mean age with respect to the general population of cats seen in the surgical pathology service
during the same time period (9.6 years versus 8.8 years;
P=0.09); also, no significant difference was found in age
with respect to tumor location.
Most (n=57; 85%) of the cats were domestic shorthairs, followed by domestic longhairs (n=5; 7.5%), unspecified rare
breeds (n=2; 3%), Siamese (n=2; 3%), and Persian (n=1;
1.5%). When compared to the general population of cats
submitted to the surgical pathology service, no breed
predilection was noted.
Breed
Of the 67 affected cats, 42 (63%) were males and 25 (37%)
were females. When compared to the surgical pathology
population, males were more frequently affected than
females (OR 1.9; 95% CIs 1.1, 3.1; P=0.014). No statistically significant difference was seen between males and
females with respect to tumor location.
Sex Distribution
Tumor location was reported in 66 of the 67 cases. Of the 41
cases in which encapsulation was noted on the submission
form, 26 (63%) of the tumors were encapsulated, and 15
(37%) were not. Involvement of regional lymph nodes,
based on physical examination, was reported in 58 cases. Of
these 58 cases, 56 (97%) had no lymph node involvement,
and two (3%) had possible involvement, although this was
not confirmed via biopsy in either case. Follow-up data
were available for one cat, which is still alive with no recurrence or metastatic disease. The tumors were generally
described (by the referring veterinarians) as white-tan, often
cavitated, glistening, and firm. Histologically, these tumors
Tumor Morphology/Histology
Table 1
Chondrosarcoma (CSA) Location in the
Axial and Appendicular Skeleton
Site
n
Bone-only
CSA (%)
Axial Skeleton
13
28
Scapula
7
15
Vertebrae
3
6.5
Pelvis
1
2.2
Sternum
2
4.3
Appendicular
Skeleton
24
Humerus
3
6.5
Radius/ulna
2
4.3
Femur
6
Tibia
4
8.7
Carpus
2
4.3
Tarsus
1
2.2
Digits
6
13
6
13
Facial
52
13
Skull
2
4.3
Mandible/maxilla
4
8.7
3
6.5
Nasal
May/June 2008, Vol. 44
The locations of tumors were further subdivided into
those from bones that develop via endochondral ossification
(i.e., vertebra, sternum, ribs, humerus, radius, ulna, femur,
tibia, carpus, tarsus, and digits) and those from bones that
undergo intramembranous ossification (i.e., facial bones,
nasal turbinates, scapula, and pelvis). Of the CSAs that
involved bones, 63% involved bones arising from endochondral ossification, and 37% involved bones arising from
intramembranous ossification [Table 2].
Twenty (30%) cases of CSA involved subcutaneous sites
and were categorized based on the following locations: axilla (5%), interscapular region (15%), thoracic region (10%),
flank (15%), lumbar area (5%), hind limb (45%), and
unspecified subcutaneous locale (5%). Histopathology
reports regarding several of the subcutaneous tumors indicated debate as to whether these tumors represented vaccine-site sarcomas. In one report, the presence of grey-blue
material within macrophages, which is consistent with vaccine product, was noted. The overall site distributions of
CSAs were 44% in long bones, 26% in flat bones, and 30%
in the subcutis [Table 2].
Information about the current status of the cat was available
for 24 cases from 1998 to 2005. The remainder of the medical records had been discarded. Eleven (45.8%) cats are
still alive with no recurrence or metastases. Most of these 11
cats had radical surgeries performed, including amputation,
hemipelvectomy, and mandibulectomy. Only one of these
11 cats had an excisional biopsy only, in which the margins
were clean; this particular tumor arose from the subcutis.
The durations of follow-up for these 11 cats ranged from 0
to 2118 days (mean 490 days).
Four (16.7%) cats are currently alive but have progression
of the primary tumor. All four of these cats had incisional
biopsies only. One of these cats with local recurrence had a
limb amputation performed 108 days later; this cat is still
alive with no recurrence after the amputation, and it is included in the two survival categories. The durations of follow-up
for these four cats ranged from 31 to 302 days (mean 167
days). (The cat that underwent amputation was excluded.)
Nine (37.5%) cats were euthanized for reasons related to
the CSA, including decreased quality of life and poor prognosis. Five of these euthanized cats had incisional biopsies;
one had a laminectomy, one had chemotherapy and radiation in addition to the excisional biopsy, and two had amputations (both of which had “dirty” surgical margins) [Table
3]. The survival times from date of diagnosis of euthanized
cats ranged from 0 to 315 days (mean 85 days). The five
euthanized cats that only had incisional biopsies survived 0
to 40 days. The cat that had the laminectomy was euthanized the day after surgery; the two that underwent amputations survived 137 and 237 days; and the cat that had an
excisional biopsy and adjuvant therapy survived 315 days.
In summary, in the nine cats that received incisional
biopsies only (i.e., effectively no treatment), four had progression of the tumor, and five were euthanized for reasons
Follow-up Information
Feline Chondrosarcoma
127
Table 2
Chondrosarcoma (CSA) Overall Site
Distribution
Bone-only
CSA (%)
All CSA
(%)
Site
n
Long Bone
29
Vertebra
3
6.5
4.5
Sternum/ribs
2
4.3
3
Humerus
3
6.5
4.5
Radius/ulna
2
4.3
4.5
Femur
6
Tibia
4
8.7
6
Carpus
2
4.3
3
Tarsus
1
2.2
1.5
Digit
6
13
9
Flat Bone
17
37
26
Skull
2
4.3
3
Mandible/
maxilla
4
8.7
6
Nasal
3
6.5
4.5
Scapula
7
Pelvis
1
Subcutis
20
63
13
15
2.2
N/A*
44
9
10.6
1.5
30
Axilla
1
1.5
Interscapular
3
4.5
Thoracic
2
3
Flank
3
4.5
Lumbar
1
1.5
Hind limb
9
13.6
Unspecified
subcutaneous
1
1.5
* N/A=not applicable
related to CSA. Fifteen cats received surgical treatment. Of
the 12 cats that had radical surgery performed, 10 (83%)
are still alive, and two (17%) were euthanized (the two
euthanized cats had “dirty” surgical margins). Three treated cats had excisional biopsies performed; one with clean
margins is still alive, and the two with “dirty” margins were
128
JOURNAL of the American Animal Hospital Association
May/June 2008, Vol. 44
Table 3
Chondrosarcoma (CSA) Treatment and Outcome: 24 Cats With Follow-up
Status and Follow-up Duration
n (% of CSA)
Tumor Site
Therapeutic Intervention
Digit
Subcutis (hind limb)
Digit
Humerus
Digit
Mandible
Scapula
Subcutis (interscapular)
Femur
Tibia
*Subcutis (hind limb)
Amputation
Hemipelvectomy
Amputation
Amputation
Amputation
Partial mandibulectomy
Amputation
Excision; margins clean
Amputation
Amputation
Amputation
Scapula
Carpus
Radius/ulna
*Subcutis (hind limb)
Incisional
Incisional
Incisional
Incisional
biopsy
biopsy
biopsy
biopsy
Subcutis (hind limb)
Maxilla
Femur
Maxilla
Nasal
Incisional
Incisional
Incisional
Incisional
Incisional
biopsy
biopsy
biopsy
biopsy
biopsy
Survival time: 1 d
Vertebra
Laminectomy/biopsy
Survival time: 137-237 d
Scapula
Amputation; incisional
biopsy after recurrence at
surgical site
Amputation; margins “dirty”
Alive with no recurrence or
metastases
Follow-up duration:
0-2118 d (mean 490 d)
11 (45.8)
Alive with progression of tumor
Follow-up duration:
31-302 d (mean 167 d)
Euthanized
Survival time: 0-40 d
4 (16.7)
9 (37.5)
Tarsus
Survival time: 315 d
Subcutis; flank
Excision, chemotherapy
(Adriamycin, Cytoxan),
radiation
* Same cat: tumor progressed after initial incisional biopsy; 108 days later, the limb was amputated with no further recurrence.
euthanized. Median survival time could not be calculated,
because 50% of the cats are alive, and the overall occurrence rate for this particular tumor is low.
Thoracic radiographs were available for 16 of the 24 follow-up cases. Almost all thoracic radiographs were taken at
the time of diagnosis; radiographs were taken in one cat
every 2 months, with no signs of metastatic disease.
Possible lung metastases were reported in only three
(18.7%) cats—two of which are still alive with no recurrence of the tumor. These cats were rechecked by the veterinarian at 563 and 918 days after radiographs were
available, and no abnormalities were noted. The third cat
May/June 2008, Vol. 44
with possible lung metastases is still alive with local progression of tumor; a recheck evaluation 31 days later found
no clinical signs associated with pulmonary disease.
Radiographs of the tumor were taken in 19 cases; the most
commonly reported findings included soft-tissue swelling
and bone lysis.
Results of blood work, reported in 18 of the 24 cases,
were normal in all but three cats. One of these three cats that
had been treated with chemotherapy was leukopenic, and
two of these cats had mildly elevated amylase.
In three of the 24 cats available for follow-up, the veterinarians reported that the locations corresponded to vaccination sites.
Although CSA is one of the more common bone tumors in
cats, its overall incidence is relatively low.2,4,5 To date, published reports on its clinical characteristics and prognosis
have been few. Much of the literature on CSA in cats consists of single case reports. In the present study, the signalment, tumor locations, and, when available, treatment
protocols and outcomes were examined.
The mean age (9.6 years) of all cats with CSA in this
study was slightly older than that in previous reports of CSA
in cats.2 The finding that most affected cats were domestic
shorthairs (85%) is consistent with the normal breed distribution in the feline population. A significant difference was
seen regarding sex distribution; males were 1.9 times more
likely to develop CSA than females. This finding is in contrast to the sex distribution in dogs with CSA, in which
females are affected 1.5 times more frequently than males.16
Although CSAs have been reported in both long bones
and flat bones, the published data are inadequate to determine site predilection in cats.2,5,15 In this study, most (46 of
67) CSAs were associated with bone; 63% involved long
bones, and 37% involved flat bones. These findings are
again in sharp contrast to site predilection in dogs, in which
61% of CSAs arise in flat bones.16 Of the long-bone CSAs
in cats, the femur and digits were the most common sites
(13% each), followed by the tibia (8.7%). The scapula was
the most commonly affected flat bone as well as the most
commonly affected of all bones (15%).
Feline CSAs do arise in vaccination sites, although
fibrosarcomas are more widely reported.12 Thirty percent of
CSAs in cats involved the soft tissues, with locations
reflecting vaccination sites, including interscapular, lateral
thorax/axilla, flank, lumbar, and hind limb. In this study, the
hind-limb subcuticular region was the most commonly
affected site. Interestingly, the hind-limb region is often the
vaccination site reserved for rabies vaccine (right rear) and
feline leukemia virus (left rear) in accordance with the
Vaccine-Associated Feline Sarcoma Task Force guidelines
set forth in 1996. In this study, vaccine product was seen in
one of these tumors, and most of the subcuticular CSAs
were suspected to be injection-related sarcomas based on
their location and often aggressive histological features.
Discussion
Feline Chondrosarcoma
129
Because only a limited number of cases were available
for follow-up, it is difficult to ascertain whether subcutaneous CSAs are more clinically aggressive than primary
bone CSAs. In fact, in the cases available, survival appeared
to depend more on the type and success of therapeutic intervention. Of the 24 cats for which follow-up information was
available, 45.8% were still alive with no recurrence of the
primary tumor or metastases. It is important to note that follow-up evaluation for evidence of metastasis was limited.
Most of the cats that were still alive with no recurrence or
metastases had undergone radical surgeries, including
amputation, hemipelvectomy, and mandibulectomy; only
one of these cats had an excisional biopsy performed, and
the margins were clean. All four of the cats with local progression of the primary tumor had only incisional biopsies
performed. Five of the nine euthanized cats had only incisional biopsies as well. One cat had an incisional biopsy and
adjuvant therapy, including radiation and chemotherapy.
Two of the nine euthanized cats had amputations, and one
had a laminectomy; in all cases, the surgical margins were
“dirty.” Moreover, the survival time from diagnosis in euthanized cats that had only an incisional biopsy was 0 to 40
days. This may reflect an unwillingness on the part of the
owner to elect more radical surgery and instead opting for
euthanasia. Interestingly, the survival times of the two cats
with amputations increased to 137 and 237 days; the cat that
received adjuvant therapy lived 315 days.
Of the three cats with reported lung masses (two of which
were followed for 1.5 to 2.5 years), none showed any clinical signs of pulmonary disease, and no lung biopsies were
performed. No cats in this study were euthanized because of
lung metastasis or metastatic disease; this is in contrast to the
situation in dogs, in which 20.5% of deaths (either from the
disease or euthanasia) are caused by lung metastases.16
The overall incidence of CSA in the feline population is
low, and the cases available were subject to the difficulties
inherent in retrospective studies and the retrieval of records
from multiple veterinary clinics. In spite of these limitations, some conclusions as to treatment and prognosis can
be drawn from the available data. In summary, CSA in cats
tends to be locally invasive but not prone to metastasize.
Cats in this study that underwent aggressive surgery had a
higher likelihood of achieving full recoveries.
Conclusion
a Version 9.1; SAS Institute, Cary, NC 27513
Footnotes
The authors thank Dr. Frances Shofer for providing the statistical analyses for this paper.
Acknowledgments
11. Slayter MV, Boosinger TR, Pool RR, Dammrich K, Misdorp W,
Larsen S. Histological classification of bone and joint tumors of
domestic animals. In: World Health Organization, Histological
Classification to Tumors of Domestic Animals. 2nd ed. Armed
Forces Institute of Pathology, Washington DC, 1994;1:11,33-35.
References
130
JOURNAL of the American Animal Hospital Association
12. Turrel JM, Pool RR. Primary bone tumors in the cat: a retrospective
study of 15 cats and a literature review. Veterinary Radiology
1982;23(4):152-166.
13. Straw RC, Withrow SJ, Gillette EL, McChesney AE. Use of radiotherapy for the treatment of intranasal tumors in cats: six cases
(1980-1985). J Am Vet Med Assoc 1986;189(8):927-929.
14. Schmidt RE, Langham RF. A survey of feline neoplasms. J Am Vet
Med Assoc 1967;151:1325-1328.
15. Liu SK, Dorfman HD, Patnaik AK. Primary and secondary bone
tumours in the cat. Small Anim Pract 1974;15:141-156.
16. Levy MS, Mauldin G, Kapatkin AS, Patnaik AK. Nonlymphoid vertebral canal tumors in cats: 11 cases (1987-1995). J Am Vet Med
Assoc 1997;210(5):663-664.
17. Alden CL, Helzer LL. Humeral chondrosarcoma in a cat. Modern
Vet Practice 1981;62:214-216.
18. Morton D. Chondrosarcoma arising in a multilobular chondroma in a
cat. J Am Vet Med Assoc 1985;186(8):804-806.
19. Yildiz F, Gurel A, Yesildere T, Ozer K. Frontal chondrosarcoma in a
cat. J Vet Science 2003;4(2):193-194.
10. Romanucci M, Bongiovanni L, Petrizzi L, Salda LD. Cutaneous
extraskeletal mesenchymal chondrosarcoma in a cat. Vet Dermatol
2005;16:121-124.
May/June 2008, Vol. 44
11. Brown NO, Patnaik AK, Mooney S, Hayes A, Harvey HJ, MacEwen
EG. Soft tissue sarcomas in the cat. J Am Vet Med Assoc
1978;173:744-749.
12. Hendrick MJ, Brooks JJ. Postvaccinal sarcomas in the cat: histology
and immunohistochemistry. Vet Pathology 1994;21:126-129.
13. Nieto A, Sanchez MA, Martinez E, Rollan E. Immunohistochemical
expression of p53, fibroblast growth factor-b, and transforming
growth factor-α in feline vaccine-associated sarcomas. Vet Pathology
2003;40:651-658.
14. Brodey RS, Riser WH, van der Heul RO. Canine skeletal chondrosarcoma: a clinicopathologic study of 35 cases. J Am Vet Med
Assoc 1974;165:68-78.
15. Thompson KG, Pool RR. Tumors of bone. In: Meuten DJ, ed.
Tumors in Domestic Animals. 4th ed. Iowa State Press, 2002:
283-290.
16. Popovitch C, Weinstein MJ, Goldschmidt MH, Shofer FS.
Chondrosarcoma: a retrospective study of 97 dogs (1987-1990). J
Am Anim Hosp Assoc 1994;30:81-85.
17. Ling GV, Morgan JP, Pool RR. Primary bone tumors in the dog: a
combined clinical, radiographic and histological approach to early
diagnosis. J Am Vet Med Assoc 1974;165:55-67.
Utility of Serum Cystatin C as a Clinical
Measure of Renal Function in Dogs
A human kit for cystatin C determination was evaluated for use with canine sera. A reference
range was also established. The association between cystatin C and glomerular filtration rate
(GFR) was evaluated in 60 dogs with various diseases, by using exogenous creatinine plasma clearance (ECPC) as a measure of GFR. The correlation between cystatin C and ECPC
(correlation coefficient [r] = -0.630; P<0.001) was stronger than the correlation between
serum creatinine and ECPC (r = -0.572; P<0.001). Nonrenal diseases (e.g., neoplasia, infection) did not influence serum cystatin C concentration. Test sensitivity was significantly better
(P<0.001) for cystatin C (76%) than for creatinine (65%). Specificities for the two tests were
87% and 91%, respectively. J Am Anim Hosp Assoc 2008;44:131-138.
Astrid Wehner, DVM
Katrin Hartmann, Dr. med. vet.,
Diplomate ECVIM-CA
Johannes Hirschberger, Dr. med. vet.,
Diplomate ECVIM-CA
(Internal Medicine, Oncology)
O
From the Department of
Small Animal Internal Medicine,
Faculty of Veterinary Medicine,
Ludwig Maximilians University Munich,
Munich, Germany 80539.
JOURNAL of the American Animal Hospital Association
Glomerular filtration rate (GFR) is widely accepted as the most accurate
measure of renal excretory function. Renal clearance is defined as the
volume of plasma that has been cleared of a particular substance per unit
of time, with GFR estimated by renal clearance of an appropriate filtration marker. The changing concentration of this marker can be measured
in plasma and urine or in plasma alone.1 However, available methods for
estimating GFR are impractical for widespread clinical use. Therefore,
serum creatinine concentration is most often used to assess renal excretory function. This test is reasonably specific but somewhat insensitive
for detecting reduced GFR.2,3 Creatinine originates from the skeletal
muscle and, to a lesser extent, food, so blood levels are influenced by
muscle mass and (to a lesser extent) food intake.2
Cystatin C is a protease inhibitor that belongs to the family of cystatines. Together with the stefines and kinogenes, the cystatines form the
super-family of cysteine proteinase inhibitors.4 The cystatin C molecule
consists of a single polypeptide chain having 120 amino acids and a
molecular weight of 13.359 kilodalton (kDa). The molecule is not glycosylated, and it has an isoelectric point of 9.3.5 Cystatin C is produced by
all nucleated cells within the body and is released during phagocytosis
and inflammation.
The major function of cystatin C is to control inflammation by inhibiting lysosomal proteases.6 Cystatin C helps to regulate intra- and extracellular protein/peptide catabolism, as well as the penetration of cancer
cells into tissues.7 Recent studies have also demonstrated antimicrobial
properties associated with this protein.4,8-10 The rate of cystatin C synthesis is constant (housekeeping type),11,12 independent of age and gender,13 and unaltered by inflammatory processes or neoplasia.11 High
concentrations can be found in serum, seminal fluid, cerebrospinal fluid
(CSF), and synovial fluid.14
Cystatin C fulfills many criteria of an ideal GFR marker, because it is
filtered by the glomeruli without any tubular secretion. The molecule
passes through the glomeruli easily because of its low molecular weight
Introduction
131
132
JOURNAL of the American Animal Hospital Association
and positive charge at physiological pH. Cystatin C is catabolized completely within the proximal tubular cells, so urine
concentration is typically low13,15 and unaltered by diseases
of the proximal tubules.16 Cystatin C is eliminated exclusively by the kidneys17 and is superior to serum creatinine
as a marker of GFR in people.13,18-21 However, few published studies explore the diagnostic utility of cystatin C in
dogs.22,23
The main goals of the present study were to validate a
human cystatin C test kit in dogs and to establish a canine
reference range. A third goal was to compare serum cystatin
C concentrations with exogenous creatinine plasma clearance (ECPC) to assess its use as a measure of renal function.
Materials and Methods
The test kit was validated using a particle-enhanced turbidimetric (PET) assaya designed to quantify cystatin C levels
in human serum or plasma. In this technique, cystatin C
binds to rabbit antihuman cystatin C antibody that has been
coupled to polystyrene particles. The resulting change in
turbidity is proportional to the cystatin C concentration in
the sample. The assay was set up on an automatic analyzerb
according to the manufacturer’s instructions.
Two serum pools were created to evaluate measures of
assay quality. One pool consisted of sera from eight dogs
with increased serum creatinine concentrations, and the
other consisted of sera from eight dogs with normal values.
Interassay variability was assessed by freezing 11 serum
samples (-80˚C) from each of the two serum pools and then
testing one daily for 10 consecutive days, with the 11th
sample thawed and tested after 365 days. Dilutional parallelism was determined by serial dilution with physiological
saline, so as to produce concentrations that were 75%, 50%,
and 25% of the original. Determining cystatin C recovery
was not possible, because a purified source of canine cystatin C was not available, and the authors’ research facilities
were not equipped to purify it.
To evaluate intraindividual variation, blood samples
were obtained at 0, 360, and 720 minutes from 27 dogs with
various degrees of kidney function. All dogs had been fasted for 12 hours.
Validation of the Test Kit
Blood samples were taken from 99 dogs presented for annual checkup examinations. All dogs had been fasted for 12
hours and had normal physical examinations, complete
blood counts, biochemical profiles, and urinalyses (i.e.,
stick, specific gravity, sediment). Blood and urine were collected by jugular vein puncture and cystocenteses, respectively. Serum samples for cystatin C measurement were
frozen (-80˚C) until analyzed.
Owners gave informed consent before any blood and
urine samples were obtained from dogs, in accordance with
published laws and university policy.
Establishment of Reference Ranges
May/June 2008, Vol. 44
Ideally, GFR should be assessed with a urinary inulin clearance, which is considered the gold standard. However, urinary clearance testing was considered impractical in a
hospital facility, so GFR was assessed by ECPC, which is a
crude but accepted substitute.24
Exogenous creatinine plasma clearance was performed
in 60 dogs that had been diagnosed with various renal and
nonrenal diseases. Of these dogs, 27 were suspected of having chronic kidney disease, with the remaining 33 being
assessed for renal function before treatment with potentially nephrotoxic substances. Final diagnoses were based on
histopathology/cytology (n=24), serology (n=11), ECPC
(n=17), and other methods (e.g., endocrine testing, abdominal ultrasonography, and echocardiography). Dogs had been
fasted for 12 hours before examination. All were clinically
well hydrated.
A standardized procedure was used to assess all 60 dogs.
First, serum creatinine concentration was determined, followed by intravenous injection with a 5% creatinine solutionc dosed at 60 to 125 mg/kg. The exact dosage depended
on body mass, with lower concentrations applied to larger
dogs. Twelve to 15 blood samples were obtained over the
next 10 hours, so that serum creatinine concentrations could
be measured enzymatically.b The upper limit of the in-house
reference range for serum creatinine was 106 µmol/L (1.2
mg/dL). The area under the curve (AUC) was calculated with
a trapezoidal approach (i.e., noncompartmental model).1
The ECPC was calculated as 100 multiplied by the
amount of injected creatinine divided by the AUC (100 ×
injected creatinine/AUC).24-26 An ECPC ≥3 mL/kg per
minute was considered normal. Values of 2.00 to 2.99
mL/kg per minute were considered to be slightly reduced,
and values ≤1.99 mL/kg per minute were considered to be
markedly reduced. These values were compared with the
reference range for cystatin C that was already established
(see above).
Comparison of Cystatin C and ECPC in Dogs
Statistical analyses were performed using version 13.0 of
SPSS.d Descriptive statistics were computed for the cystatin
C test kit validation and reference range calculations.
Kolmogorov-Smirnov analysis was used to determine if the
age and gender variables used in the reference range calculations were normally distributed and if the reference range
itself was normally distributed. Pearson’s correlation statistics were used to assess the association between cystatin C
and age, weight, or gender. Correlational analysis was also
used to assess the relationships between ECPC and serum
creatinine, between ECPC and cystatin C, and between
serum cystatin C and presence of nonrenal disease.
Receiver operating characteristics (ROC) analysis was
used to compare sensitivity, specificity, and positive/negative predictive values for both serum cystatin C and
serum creatinine. Sensitivity is defined as true positives
divided by the sum of true positives and false negatives, and
Statistics
May/June 2008, Vol. 44
Cystatin C in Renal Function Testing
133
B
A
Figures 1A, 1B—Correlation between the observed and calculated cystatin C concentrations of different dilutions of
pooled canine sera (1A=pool with higher concentrations, n=8; 1B=pool with normal concentrations, n=8).
specificity is defined as true negatives divided by the sum of
false positives and true negatives. Positive predictive value
is defined as true positives divided by the sum of true positives and false positives, and negative predictive value is
defined as true negatives divided by the sum of true negatives and false negatives. Statistical significance was defined
as P<0.05.
Results
The intraassay coefficients of variation were 1.76% for the
serum pool consisting of the eight dogs with high creatinine values, and 3.85% for the serum pool consisting of the
Validation of the Test Kit
eight dogs with normal values. The interassay coefficients
of variation for these two groups were 2.95% and 3.64%,
respectively [see Table]. Values for the two serum pools
were 8% and 11% higher (respectively) after 365 days. An
almost linear decrease in cystatin C concentration was
observed after serial dilution (75%, 50%, 25%). The correlation coefficient (r) was 0.992 (P<0.01) for those with
high creatinine, and r was 0.989 (P<0.05) for those with
normal creatinine [Figures 1A, 1B].
Serum cystatin C concentrations remained stable over time
in the 27 dogs sampled at 0, 360, and 720 minutes (r=0.964,
0.954, respectively; P<0.001).
Intraindividual Variations
Table
Intra- and Interassay Variability for the Cystatin C PET* Kit in Two Pools† of Canine Sera
Cystatin C Concentrations
Intraassay Variability
Pooled Sera Used
Mean (mg/L)
Standard deviation
Coefficient of variation (%)
Number of replicates
Interassay Variability
High Creatinine
Normal Creatinine
High Creatinine
Normal Creatinine
2.177
0.038
1.759
10
1.607
0.061
3.847
10
1.967
0.057
2.945
10
1.461
0.053
3.642
10
* PET=particle-enhanced turbidimetric
† One pool was from dogs (n=8) with high serum creatinine concentrations, and another was from dogs (n=8) with normal serum
creatinine concentrations.
134
JOURNAL of the American Animal Hospital Association
The 99 reference dogs ranged in age from 3 months to 13
years (median 4 years). Twenty-five dogs were intact
females, 27 were spayed females, 26 were intact males, and
21 were neutered males. Body weight ranged from 5 to 42
kg (median 25 kg). Kolmogorov-Smirnov analysis suggested that age and weight were normally distributed. Breeds
represented by more than one case in the reference group
were German shepherd dog (n=18); golden retriever (n=8);
Labrador retriever (n=6); dachshund (n=4); Magyar vizsla,
border collie, Belgian Tervuren, Dalmatian, Siberian husky
(n=3 each); and Bernese mountain dog, Irish wolfhound,
Schapendoes, boxer, and rottweiler (n=2 each). The remaining 38 cases consisted of other breeds (n=12) or mixed
breeds (n=26).
Serum cystatin C concentrations ranged from 0.49 to
1.81 mg/L (mean 1.144, standard deviation [SD] ± 0.231).
The 0.025 and 0.975 quantiles (determined as mean ± 2 SD)
were 0.682 mg/L and 1.606 mg/L, respectively, suggesting
a reference range of 0.68 to 1.6 mg/L. KolmogorovSmirnov analysis suggested that cystatin C values were normally distributed.
Serum creatinine concentrations for the 99 dogs ranged
from 56 to 103 µmol/L (0.63 to 1.17 mg/dL), with a mean ±
SD of 81.90±13.29 µmol/L. A serum creatinine reference
range for these 99 dogs would be 55.31 to 108.5 µmol/L
(0.63 to 1.23 mg/dL), based on 0.025 and 0.975 quantiles.
This almost matched the established in-house reference
range, so the upper limit for serum creatinine was left as the
in-house value of 106 µmol/L (1.2 mg/dL).
Establishment of Reference Values
No significant correlation was found between serum cystatin C and age (r=0.022; P>0.05) or between cystatin C and
weight (r=0.036; P>0.05). Serum cystatin C concentrations
were similar in the 52 female (mean ± SD 1.13±0.24 mg/L)
and 47 male (mean ± SD 1.15±0.21 mg/L) dogs [Figure 2].
Influence of Age, Weight, and Gender
May/June 2008, Vol. 44
The Mann-Whitney U test and Wilcoxon’s test confirmed
that the cystatin C distributions were similar between males
and females.
The ages for these 60 dogs ranged from 0.5 to 15 years
(median 5 years), and the weights ranged from 7 to 51.8 kg
(median 27.2 kg). Twenty-five females (16 spayed) and 35
males (eight neutered) were represented. Breeds that were
represented by more than one case were Bernese mountain
dog (n=6), boxer (n=4), beagle (n=3), German shepherd dog
(n=3), and West Highland white terrier (n=2). The remainder consisted of other purebred (n=15) or mixed-breed
(n=27) dogs. These dogs were ultimately diagnosed with
neoplasia (n=7), chronic kidney disease (n=24), neoplasia
and concurrent chronic kidney disease (n=15), infection
(n=10), or four other diseases (two endocrinopathies, one
psychogenic drinker, and one mitral insufficiency).
Serum creatinine values for these 60 dogs ranged from
42 to 590 µmol/L (0.46 to 6.67 mg/dL), with a median of 91
µmol/L. Forty-three percent of these values were above the
reference range (i.e., >106 µmol/L [>1.2 mg/dL]). Cystatin
C values ranged from 0.79 to 5.97 mg/L (median 1.65
mg/L), with 52% having elevated concentrations (>1.6
mg/L). Results of ECPC ranged from 0.3 to 5.0 mL/kg per
minute (median 2.6 mL/kg per minute), with 38% (23 of 60)
dogs having normal (≥3 mL/kg per minute) values, and 62%
(37 of 60) having abnormal values. The abnormal ECPC
values consisted of slightly decreased ECPC (i.e., 2.00 to
2.99 mL/kg per minute) in 22 dogs and markedly decreased
ECPC (≤1.99 mL/kg per minute) in 15 dogs.
Comparison of Cystatin C and ECPC in Dogs
A significant inverse correlation was seen between ECPC
and serum creatinine in these 60 dogs (r= -0.572; P<0.001),
which appeared less than linear [Figure 3A]. Also, a significant and less than linear inverse correlation (r= -0.630;
P<0.001) was seen between ECPC and serum cystatin C,
but the relationship appeared more linear than the one
between ECPC and creatinine [Figure 3B]. A strong and significant positive correlation (r=0.886; P<0.001) was seen
between serum creatinine and serum cystatin C, which
approached linearity [Figure 4].
Correlation Among ECPC, Creatinine, and Cystatin C
Correlation Between Creatinine or Cystatin C and the
Degree of Renal Function
Figure 2—Cystatin C concentrations (mean ± standard
deviation [SD]) of 99 clinically normal dogs (52 female and
47 male) used to establish a reference range.
Dogs were assigned to three groups according to the results
of the ECPC. Group 1 had normal ECPC (≥3 mL/kg per
minute; n=23); group 2 had slightly reduced ECPC (2.00 to
2.99 mL/kg per minute; n=22); and group 3 had markedly
reduced ECPC (≤1.99 mL/kg per minute; n=15). Serum creatinine and cystatin C concentrations were compared within these groups [Figures 5A, 5B]. The median serum
concentration of cystatin C in dogs with slightly reduced
ECPC (Group 2) was outside the reference range, while the
median serum creatinine concentration was within the reference range. All dogs with markedly reduced ECPC
May/June 2008, Vol. 44
Cystatin C in Renal Function Testing
A
135
Figure 4—Correlation between serum creatinine and
serum cystatin C concentrations in 60 dogs with various
diseases.
Sensitivity, Specificity, ROC Analysis, Positive and
Negative Predictive Values
The sensitivity for detecting decreased ECPC (<3.0 mL/kg
per minute) was 76% for cystatin C, but sensitivity was only
65% for serum creatinine (P<0.001). Specificities were similar between serum cystatin C (87%) and serum creatinine
(91%). The ROC analysis suggests that cystatin C is significantly better (P<0.001) than serum creatinine at identifying
reduced ECPC [Figure 7]. The positive and negative predictive values for detecting decreased ECPC were 90% and
69% (respectively) for serum cystatin C, and they were 92%
and 62% (respectively) for serum creatinine.
B
Figures 3A, 3B—Correlation between exogenous creatinine plasma clearance (ECPC) and either serum creatinine
concentrations or serum cystatin C concentrations in 60
dogs with various diseases. The area between the vertical
black lines indicates mild kidney disease. The dashed lines
indicate the upper reference ranges for serum creatinine
and serum cystatin C.
(Group 3) had elevated serum cystatin C concentrations, but
some had normal serum creatinine values.
Dogs were assigned to five groups according to their final
diagnosis. Cystatin C concentrations in the different groups
were compared to explore the influence of nonrenal diseases on cystatin C. Almost all dogs with nonrenal diseases
and normal GFR had cystatin C values within the reference
range [Figure 6], and all such dogs had normal creatinine
values.
Comparison of Cystatin C Among Final Diagnoses
Identification of renal disease is important in canine medicine, but early diagnosis remains difficult in some cases.
Serum creatinine concentration rises as GFR falls, but
azotemia is not usually clinically apparent in dogs until
GFR decreases by ≥75%. Therefore, creatinine screening
tests may not detect mildly decreased renal function. Mild
kidney disease in dogs can be reliably diagnosed only by
performing time-consuming clearance procedures, such as
ECPC or iohexol plasma clearance. In contrast, human studies have focused on endogenous, low-molecular-weight
proteins as a way to detect early renal dysfunction.18
Multiple studies of GFR reduction in people have shown
that serum cystatin C concentration has better sensitivity
and negative predictive value than serum creatinine.16,27-30
The authors’ study suggests that the human PET assaya is
valid for measuring cystatin C in dogs. This test is rapid,
precise, and inexpensive. It measures cystatin C in a linear
and proportional manner, which is consistent with results of
other veterinary studies.22,23 Unfortunately, the authors
were unable to determine percent recovery at their facility.
This is a limitation of this study, in that the authors were not
Discussion
136
JOURNAL of the American Animal Hospital Association
A
B
Figures 5A, 5B—Serum creatinine and serum cystatin C
concentrations in 60 dogs with various diseases, according
to renal function as defined by exogenous creatinine plasma clearance (ECPC) measurement. The dashed lines
indicate the upper reference ranges for creatinine and cystatin C. Normal renal function is defined as ECPC ≥3
mL/kg per minute; slightly impaired renal function is
defined as ECPC 2.00 to 2.99 mL/kg per minute; and
markedly impaired renal function is defined as ECPC ≤1.99
mL/kg per minute.
able to definitively prove that the PET assay was measuring
cystatin C.
The exact genetic structure of canine cystatin C is
unknown, but a high degree of homology appears to exist
between people, cattle, mice, and rats. One genetic
sequence (i.e., the so-called µ-trace) has a high degree of
homology between people and dogs.31-35 The authors
hypothesized that the PET assay might reliably detect
May/June 2008, Vol. 44
Figure 6—Serum cystatin C concentrations in 60 dogs
with different diseases. The dashed line indicates the
upper reference range for cystatin C; CKD=chronic kidney
disease.
Figure 7—Nonparametric receiver operating characteristics (ROC) plots of percent sensitivity and specificity for
discriminating between normal and reduced exogenous
creatinine plasma clearance (ECPC). The sensitivity of
serum cystatin C is significantly (P<0.001) higher than that
of serum creatinine in 60 dogs with various diseases.
canine cystatin C, given this homology between people and
dogs and the high degree of correlation between the PET
assay and renal function.
This study demonstrated that serum cystatin C is stable
over time and can be reliably measured after being frozen at
-80˚C for 1 year. The same has been shown in people.36
High concentrations of proteinase inhibitors (e.g., α2macroglobulin, α1-protease inhibitor, and kinogenes) and
natural preservatives, such as transferrin, add stability to the
blood.18
The reference range for cystatin C in this study was 0.68 to
1.6 mg/L, which is slightly above the range observed in other
veterinary and human studies.22,23,37-39 This slight difference
May/June 2008, Vol. 44
may have been caused by slight variations in the assay principle or reagents or by differences in instrumentation.
Ideally, a GFR measurement should have been performed in the population used to establish the cystatin C reference range, in order to assure that all test dogs truly had
normal renal excretory function. However, the 99 dogs used
to establish the reference range in this study had no medical
complaints and were considered healthy based on physical
and laboratory examinations. Further workup (including
GFR) on healthy dogs would have also required a petition
to the government for an animal experimentation permit.
For these reasons, the authors opted to forgo simultaneous
assessment of GFR. Standard convention was followed, and
the reference range was based on the 0.025 and 0.975 quantiles, which excluded extreme values and decreased the likelihood of including dogs with early, undetected, chronic
kidney disease.
Age, body weight, and gender did not influence cystatin
C concentration, suggesting no need to calculate ranges
dependent on these variables. These findings are similar to
those of human studies,40-42 but contrary to those of one
veterinary study.39 However, no GFR measurements were
performed in that veterinary study,39 suggesting that the
possible inclusion of early kidney disease could have
impacted the results.
The authors observed low intraindividual cystatin C variation over time, which is an advantage for this test. Low
intraindividual variation simplifies the collection of samples,
which do not need to be drawn at any specific time of day.
Studies in dogs suggest that GFR increases significantly
after protein ingestion.43 All dogs in this study were fasted,
so the authors could not investigate the effects of food on
cystatin C levels. In a human study, cystatin C remained relatively stable despite food consumption.41 However, a
study in dogs demonstrated a significant decrease in cystatin C levels after feeding.39 This discrepancy might be
explained by the different protein concentrations in human
meals compared with those in dog food. More data are
needed that examine the impact of feeding on serum cystatin C concentrations in dogs.
None of the dogs in this study had acute kidney disease.
In people with acute kidney disease, serum cystatin C levels
rise earlier than serum creatinine levels and correlate better
with GFR.44-46 No published veterinary studies have analyzed serum cystatin C in the presence of acute kidney disease, but volume depletion might mimic this condition.
Almy et al.23 showed that dogs with volume depletion had
cystatin C concentrations within the reference range, despite
a mildly reduced GFR. However, it is not known if volume
depletion adequately reflects acute kidney disease. More
studies are needed to investigate the influence of acute kidney disease, volume depletion, and postrenal azotemia on
serum cystatin C concentration.
In this study, serum cystatin C correlated better with
ECPC (r= -0.630; P<0.001) than did serum creatinine
(r= -0.572; P<0.001), suggesting that cystatin C is probably
a more sensitive test of reduced GFR. In other words, in
dogs with early renal impairment, cystatin C concentrations
Cystatin C in Renal Function Testing
137
will probably increase before serum creatinine concentrations. This is borne out in this study by the 76% sensitivity
for detecting reduced GFR, which is 11% higher than that of
serum creatinine. Although a sensitivity of 80% or 90%
would be more desirable, currently no better test is available
to diagnose early renal excretory dysfunction from a single
canine blood sample.
Cystatin C and creatinine have similar positive predictive
values. However, the higher negative predictive value for
serum cystatin C (69%) compared with that of serum creatinine (62%) will result in fewer false negatives, suggesting a
better screening test for early canine kidney disease.
The slightly better specificity of serum creatinine (91%)
over serum cystatin C (87%) makes the authors reluctant to
recommend complete replacement of serum creatinine testing at this time. Using both tests simultaneously should
enhance diagnostic accuracy for kidney disease. The similar
specificities for both parameters in this study suggest the
need for additional studies that confirm the superior specificity of serum creatinine.
In this study, serum cystatin C was not influenced by
neoplasia or infection. Although cystatin C is involved in
inflammation and spread of cancer cells, studies in people
have not found that these conditions alter serum concentrations;11,12 results of this current study agree. However, the
authors examined only a limited number of dogs with neoplastic or infectious disease, suggesting that more data are
needed to better assess the impact of these diseases on
serum cystatin C concentration.
Endogenous, low-molecular-weight proteins could serve as
a practical way to rapidly detect early kidney disease.
Canine cystatin C was reliably measured with the human
PET assay,a independent of age, body weight, gender, or the
presence of neoplastic/infectious disease. Serum cystatin C
correlated slightly better with ECPC than did serum creatinine. Cystatin C had a higher sensitivity and negative predictive value than did serum creatinine, making it a better
screening test for early canine kidney disease. The slightly
better specificity of serum creatinine suggests that both cystatin C and creatinine should be measured simultaneously in
order to enhance diagnostic accuracy for detecting (or
excluding) canine renal excretory dysfunction.
Conclusion
a Particle-enhanced turbidimetric (PET) assay; Dako, Glostrup, Denmark
b Hitachi 911 automatic analyzer; Roche, Mannheim, Germany
c Creatinine anhydrous 5% solution; Sigma-Aldrich, Hamburg, Germany
d SPSS 13.0; SPSS Inc., Chicago, IL 60606
Footnotes
The authors thank Drs. Michael D. Willard and George E.
Less for their contributions to the manuscript.
Acknowledgments
11. Heiene R, Moe L. Pharmacokinetic aspects of measurement of
glomerular filtration rate in the dog: a review. J Vet Intern Med
1998;12:401-414.
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12. Braun JP, Lefebvre HP, Watson AD. Creatinine in the dog: a review.
Vet Clin Pathol 2003;32:162-179.
13. Perrone RD, Madias NE, Levey AS. Serum creatinine as an index of
renal function: new insights into old concepts. Clin Chem
1992;38:1933-1953.
14. Barrett AJ, Davies ME, Grubb A. The place of human gamma-trace
(cystatin C) amongst the cysteine proteinase inhibitors. Biochem
Biophys Res Commun 1984;120:631-636.
15. Grubb A, Lofberg H. Human gamma-trace, a basic microprotein:
amino acid sequence and presence in the adenohypophysis. Proc Natl
Acad Sci USA 1982;79:3024-3027.
16. Warfel AH, Zucker-Franklin D, Frangione B, et al. Constitutive
secretion of cystatin C (gamma-trace) by monocytes and
macrophages and its downregulation after stimulation. J Exp Med
1987;166:1912-1917.
17. Hall A, Hakansson K, Mason RW, et al. Structural basis for the biological specificity of cystatin C. Identification of leucine 9 in the Nterminal binding region as a selectivity-conferring residue in the
inhibition of mammalian cysteine peptidases. J Biol Chem
1995;270:5115-5121.
18. Korant BD, Brzin J, Turk V. Cystatin, a protein inhibitor of cysteine
proteases alters viral protein cleavages in infected human cells.
Biochem Biophys Res Commun 1985;127:1072-1076.
19. Bjorck L, Grubb A, Kjellen L. Cystatin C, a human proteinase
inhibitor, blocks replication of herpes simplex virus. J Virol
1990;64:941-943.
10. Collins AR, Grubb A. Inhibitory effects of recombinant human cystatin C on human coronaviruses. Antimicrob Agents Chemother
1991;35:2444-2446.
11. Randers E, Kornerup K, Erlandsen EJ, et al. Cystatin C levels in sera
of patients with acute infectious diseases with high C-reactive protein levels. Scand J Clin Lab Invest 2001;61:333-335.
12. Lah TT, Kokalj-Kunovar M, Strukelj B, et al. Stefins and lysosomal
cathepsins B, L and D in human breast carcinoma. Int J Cancer
1992;50:36-44.
13. Simonsen O, Grubb A, Thysell H. The blood serum concentration of
cystatin C (gamma-trace) as a measure of the glomerular filtration
rate. Scand J Clin Lab Invest 1985;45:97-101.
14. Brzin J, Popovic T, Turk V, et al. Human cystatin, a new protein
inhibitor of cysteine proteinases. Biochem Biophys Res Commun
1984;118:103-109.
15. Grubb A, Lofberg H. Human gamma-trace. Structure, function and
clinical use of concentration measurements. Scand J Clin Lab Invest
Suppl 1985;177:7-13.
16. Herget-Rosenthal S, Trabold S, Pietruck F, et al. Cystatin C: efficacy
as screening test for reduced glomerular filtration rate. Am J Nephrol
2000;20:97-102.
17. Tenstad O, Roald AB, Grubb A, et al. Renal handling of radiolabelled human cystatin C in the rat. Scand J Clin Lab Invest
1996;56:409-414.
18. Grubb A, Simonsen O, Sturfelt G, et al. Serum concentration of cystatin C, factor D and beta 2-microglobulin as a measure of glomerular filtration rate. Acta Med Scand 1985;218:499-503.
19. Pergande M, Jung K. Sandwich enzyme immunoassay of cystatin C
in serum with commercially available antibodies. Clin Chem
1993;39:1885-1890.
20. Newman DJ, Thakkar H, Edwards RG, et al. Serum cystatin C measured by automated immunoassay: a more sensitive marker of
changes in GFR than serum creatinine. Kidney Int 1995;47:312-318.
21. Kyhse-Andersen J, Schmidt C, Nordin G, et al. Serum cystatin C,
determined by a rapid, automated particle-enhanced turbidimetric
method, is a better marker than serum creatinine for glomerular filtration rate. Clin Chem 1994;40:1921-1926.
22. Jensen AL, Bomholt M, Moe L. Preliminary evaluation of a particleenhanced turbidimetric immunoassay (PETIA) for the determination
of serum cystatin C-like immunoreactivity in dogs. Vet Clin Pathol
2001;30:86-90.
23. Almy FS, Christopher MM, King DP, et al. Evaluation of cystatin C
as an endogenous marker of glomerular filtration rate in dogs. J Vet
Intern Med 2002;16:45-51.
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24. Watson AD, Lefebvre HP, Concordet D, et al. Plasma exogenous creatinine clearance test in dogs: comparison with other methods and
proposed limited sampling strategy. J Vet Intern Med 2002;16:22-33.
25. Hochel J, Finnah A, Velde K, et al. [Evaluation of a modified exogenous creatinine clearance as a suitable renal function test for the
small animal practice]. Berl Munch Tierarztl Wochenschr
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26. Kerl ME, Cook CR. Glomerular filtration rate and renal scintigraphy.
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27. Christensson A, Ekberg J, Grubb A, et al. Serum cystatin C is a more
sensitive and more accurate marker of glomerular filtration rate than
enzymatic measurements of creatinine in renal transplantation.
Nephron Physiol 2003;94:19-27.
28. Helin I, Axenram M, Grubb A. Serum cystatin C as a determinant of
glomerular filtration rate in children. Clin Nephrol 1998;49:221-225.
29. Nitta K, Hayashi T, Uchida K, et al. Serum cystatin C concentration
as a marker of glomerular filtration rate in patients with various renal
diseases. Intern Med 2002;41:931-935.
30. Wasen E, Isoaho R, Mattila K, et al. Estimation of glomerular filtration rate in the elderly: a comparison of creatinine-based formulae
with serum cystatin C. J Intern Med 2004;256:70-78.
31. Poulik MD, Shinnick CS, Smithies O. Partial amino acid sequences
of human and dog post-gamma globulins. Mol Immunol
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32. Colle A, Tonnelle C, Jarry T, et al. Isolation and characterization of
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33. Esnard A, Esnard F, Faucher D, et al. Two rat homologues of human
cystatin C. FEBS Lett 1988;236:475-478.
34. Hirado M, Tsunasawa S, Sakiyama F, et al. Complete amino acid
sequence of bovine colostrum low-Mr cysteine proteinase inhibitor.
FEBS Lett 1985;186:41-45.
35. Sekine T, Poulik MD. Post-gamma globulin: tissue distribution and
physicochemical characteristics of dog post-gamma globulin. Clin
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36. Erlandsen EJ, Randers E, Kristensen JH. Evaluation of the Dade
Behring N Latex cystatin C assay on the Dade Behring
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37. Bokenkamp A, Domanetzki M, Zinck R, et al. Reference values for
cystatin C serum concentrations in children. Pediatr Nephrol
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38. Finney H, Newman DJ, Price CP. Adult reference ranges for serum
cystatin C, creatinine and predicted creatinine clearance. Ann Clin
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39. Braun JP, Perxachs A, Pechereau D, et al. Plasma cystatin C in the
dog: reference values and variations with renal failure. Vet Clin Path
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40. Bokenkamp A, Domanetzki M, Zinck R, et al. Cystatin C—a new
marker of glomerular filtration rate in children independent of age
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41. Cimerman N, Brguljan PM, Krasovec M, et al. Twenty-four hour
variations of cystatin C and total cysteine proteinase inhibitory activity in sera from healthy subjects. Clin Chem Acta 2000;291:89-95.
42. Norlund L, Fex G, Lanke J, et al. Reference intervals for the
glomerular filtration rate and cell-proliferation markers: serum cystatin C and serum beta 2-microglobulin/cystatin C-ratio. Scand J Clin
Lab Invest 1997;57:463-470.
43. Brown SA, Finco DR. Characterization of the renal response to protein ingestion in dogs with experimentally induced renal failure. Am
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for noninvasive estimation of glomerular filtration rate and as a
marker for early renal impairment. Am J Kidney Dis 2000;36:29-34.
Primary Osseous Melanoma
in the Tibia of a Dog
An 18-month-old, female Cane Corso dog was presented with a suspected primary tumor of
the tibia. Plain radiographs and computed tomography (CT) of the tibia were highly suggestive of a primary bone neoplasm. A diagnosis of malignant melanoma was made by cytology.
Total body survey radiographs, CT scan of the thorax, and abdominal ultrasound excluded
the presence of neoplastic lesions other than in the tibia. Limb amputation was performed.
Histology and immunohistochemical analysis of the tibial neoplasm confirmed the diagnosis
of a melanoma with secondary metastasis to the popliteal lymph node. The dog was alive
and in good physical condition 43 months after surgery. J Am Anim Hosp Assoc 2008;44:139-143.
Damiano Stefanello, DVM, PhD
Stefano Romussi, DVM, PhD
Paola Signorelli, DVM, PhD
Mario Caniatti, DVM,
Diplomate ECVP
Mauro DiGiancamillo, DVM
Paola Roccabianca, DVM,
Diplomate ECVP
Giancarlo Avallone, DVM
C
From the Department of Veterinary
Clinical Sciences (Stefanello, Romussi,
Signorelli, DiGiancamillo)
and the Department of Veterinary
Pathology, Hygiene, and Public Health
(Caniatti, Roccabianca, Avallone),
School of Veterinary Medicine,
University of Milan,
Via Celoria 10, Milan, 20133, Italy.
JOURNAL of the American Animal Hospital Association
Introduction
Osteosarcoma is the most common appendicular skeletal neoplasm in
dogs, accounting for approximately 80% of canine primary bone
tumors.1 Chondrosarcoma, fibrosarcoma, and hemangiosarcoma are
reported to be the most prevalent nonosteogenic primary tumors of the
canine appendicular skeleton.1 Other reported primary tumors of bone
are less common and include liposarcoma, lymphoma, myeloma, giant
cell tumor of bone, and malignant fibrous histiocytoma.1,2 Primary
appendicular skeletal neoplasms are more common in large breeds.1
Older dogs are generally affected, although a biphasic peak (2 and 9
years) has been reported for osteosarcoma.1
Canine melanoma most frequently affects the oral cavity, mucocutaneous junctions, nail bed, skin, and eye.3-7 A poor prognosis is associated
with the first three anatomical locations, due to local infiltration and
development of distant metastases.3,4,8 Typically, primary cutaneous and
ocular melanomas have a better prognosis than those in the oral cavity.4,6,7
In dogs, the development of distant metastases has been described for
most internal organs, but metastases are more common in regional lymph
nodes and lungs.9 In veterinary medicine, reports of bone metastasis from
distant primary sites is limited, but prostate, mammary gland, and urinary
bladder tumors are most often the sources of bone metastasis.10
Occasionally, metastases of melanomas to bone have been reported, but
the authors are unaware of previous cases of primary osseous melanoma
in dogs.
This report describes the clinical, radiological, and pathological findings in a dog with primary osseous melanoma.
Case Report
An intact female Cane Corso dog was evaluated at 11 months of age by
a private practitioner for a moderate lameness of the right hind limb.
Radiographs of the coxofemoral and stifle joints under general anesthesia were made and interpreted as normal. The dog was discharged with
carprofen (2 mg/kg per os [PO] q 12 hours for 10 days). The lameness
progressively worsened, and 6 months after initial presentation, the dog
underwent reevaluation by the same practitioner. A painful 2 cm by 2 cm
139
140
JOURNAL of the American Animal Hospital Association
swelling of the proximal tibia was noted. Nail beds and
digits were clinically normal. No bone lysis of the phalanxes was observed on radiographs made at that time.
Based on radiographic findings, a primary osteosarcoma or
an osteomyelitis was suspected. The dog was discharged
with no therapy.
At 18 months of age, 30 days after the second evaluation,
the dog was referred for a second opinion. On physical
examination, the dog was severely lame, and a painful softtissue swelling (10 cm by 5 cm) of the right proximal tibia
was found. Radiographic examination revealed an extensively lytic lesion associated with a pathological fracture of
the tibial diaphysis, with disorganized periosteal proliferation. Transitional areas were enlarged and poorly defined
[Figure 1].
A free-hand fine-needle aspiration biopsy from the
lesion was performed with a 21-gauge needle. Clear fluid
(2 mL) was collected and submitted for cytology.
Cytological specimens were highly cellular and characterized by a population of pleomorphic cells. Cells were round
to polygonal to spindle-shaped, and they were occasionally
organized in highly cohesive groups. Cells had distinct borders and light-blue cytoplasm. Variable amounts of finely
granular, black pigment (i.e., melanin) were present in
cytoplasm. Nuclei were round with finely dispersed chromatin and one to two nucleoli. Rare atypical mitotic figures
were present. Occasionally, atypical multinucleated giant
cells (two to six nuclei) were detected. Foamy, reactive
macrophages often containing coarsely clumped melanin
(i.e., melanomacrophages) were also observed [Figure 2].
Based on cytology, a melanoma was diagnosed. To better
evaluate the extent of the tumor, computed tomography
(CT) was performed with a fourth-generation scanner.a
Transverse, 5-mm, contiguous slices of the right tibia were
obtained. Pre- and postcontrast examinations, using a bolus
intravenous (IV) injection of 600 mg/kg body weight of
nonionic iodine contrast medium, were performed.
Reformatted dorsal and sagittal planes were also obtained.
Regions of interest were drawn in the medullary cavity
(i.e., center of the lesion), in the abnormal perilesional soft
tissues, and in the muscle tissue not invaded by the neoplasm. Density attenuation data were measured before and
after contrast medium administration. The CT study showed
a space-occupying mass characterized by a precontrast
mean attenuation value of 62.7 Hounsfield unit (HU). The
mass was located mainly in the medullary cavity and invaded the surrounding tissues that were characterized by
hypoattenuated areas [Figure 3A]. The mass showed a
strong contrast enhancement with a peak attenuation value
of 161.5 HU. The contrast medium examination better
demonstrated the heterogeneous soft-tissue swelling secondary to multifocal necrosis [Figure 3B].
A complete clinical examination was performed to
exclude metastatic disease from a primary melanoma. The
dog underwent ophthalmological, dermatological (including mucocutaneous junctions and nail beds), and oral cavity examinations. Clinical staging of the neoplasm included
May/June 2008, Vol. 44
Figure 1—Medial-lateral radiograph of the right tibia in an
18-month-old, female Cane Corso dog demonstrating an
osteolytic lesion with extensive destruction of the cortex
and soft-tissue swelling (arrow). Note the very large transitional area (arrowhead).
Figure 2—Photomicrograph of a fine-needle aspirate of
the right tibial lesion. The biopsy sample is highly cellular,
characterized by round to spindle-shaped cells.
Cytoplasmic, granular black pigment (melanin) is evident
in some neoplastic cells (arrows). An osteoclast is also
present (arrowhead). (Giemsa d stain, 1000×; bar=30 µm)
total body survey radiographs, CT scan of the thorax, and
abdominal ultrasound. No paronychia, nail deformity, or
nail loss were observed. No lesions other than in the tibia
were detected. Amputation of the right hind limb at the
coxofemoral joint was performed.
The entire leg, including the popliteal lymph node, was
submitted for histopathological examination. No gross
lesions were found in the skin, nails, or nail beds. Histology
revealed severe and diffuse bone lysis with substitution and
effacement of the compact bone and the medullary cavity by
a densely cellular population of neoplastic cells. Cells were
organized in nests and cords embedded in abundant
fibrovascular stroma. Anisocytosis was prominent, and cells
were round to spindle-shaped with distinct cell borders and
May/June 2008, Vol. 44
Primary Osseous Melanoma in a Dog
141
A
Figures 3A, 3B—Computed tomographic images of the
proximal aspects of the right tibia. (A) Precontrast image,
showing severe absence of the cortex and a moderate
periosteal response in the lateral aspect of the tibia
(arrow). Rounded, slightly hyperattenuated area (67 HU) is
present in the medullary cavity (arrowhead). (B) Postcontrast image, showing the high enhancement (200 HU)
in the medullary cavity and replacement by the tumorous
tissue following intravenous contrast medium (arrowhead).
B
variably abundant, lightly eosinophilic cytoplasm. Variable
numbers of cytoplasmic, black, fine granules were present
in approximately 30% of the cells. Nuclei were round with
finely dispersed chromatin and one to two magenta, round
to triangular nucleoli. Mitotic figures ranged from zero to
two per 400-magnification field. Multifocal necrosis and
accumulation of melanomacrophages were evident [Figure
4]. A diagnosis of lightly pigmented, epithelioid-type
melanoma was made. The popliteal lymph node was characterized by expansion of corticomedullary sinuses. One portion of the cortex was completely substituted by cohesive
cells with similar morphology as the bone tumor.
Immunohistochemical analysis was performed on the bone
lesion and on the popliteal lymph node. Atypical cells
stained positive for vimentin, neuron-specific enolase, S 100
Figure 4—Photomicrograph of the osseous melanoma,
showing densely packed sheets of spindle (small, white
arrows) to polygonal cells (small, black arrow) surrounded
by fibrovascular stroma (large, black arrows). Cells are
characterized by variable amounts of cytoplasmic, granular
to clumped black pigment (arrowheads). (Hematoxylin
stain, 200×; bar=200 µm)
protein, and Melan A protein [Figure 5]. Cells stained negative for cytokeratin, factor VIII, actin, and glial fibrillary
acidic protein. These immunohistochemical findings were
consistent with melanoma.
A final diagnosis of primary osseous melanoma with
metastasis to the popliteal lymph node was made based on
clinicopathological, ultrasonographic, and radiotomographic findings.
The dog rapidly improved after surgery and was discharged with a guarded prognosis. The owner refused adju-
Figure 5—Photomicrograph of the osseous melanoma,
showing intense cytoplasmic, Melan A positive staining of
neoplastic cells (arrowheads), identified as red chromogen/aminoethylcarbazole. (Hematoxylin counterstain,
100×; bar=100 µm)
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May/June 2008, Vol. 44
JOURNAL of the American Animal Hospital Association
vant chemotherapy for the dog. Regular follow-ups (every 4
months) included routine clinical examinations and chest
and abdominal radiographs. The patient was alive and in
good physical condition 43 months after surgery.
Discussion
This case seems to be the first report of primary bone
melanoma in a dog.1 The dog of this report survived for an
extended period (at least 43 months). This is in contrast to
the poor prognosis associated with malignant melanoma in
the oral cavity or nail bed.3,5,12,13
Distant metastases of malignant melanoma are most frequently to regional lymph nodes and lungs.9 Secondary
involvement of vertebrae, ribs, and radius has occasionally
been documented in association with melanomas of the lips,
eyes, and digits.3,9-12,14 In this dog, the main challenge was
to define with certainty the primary intraosseous origin of
the tumor. The main differential diagnosis was a primary
nail bed melanoma.
Nail bed melanomas are generally diagnosed in dogs
with a mean age of 9.3 years (range 5 to 13 years). The dog
in this case was younger (1.5 years).15 The clinical findings
considered typical of nail bed melanoma (such as paronychia, nail deformity, and nail loss9) were not present in this
case. Additionally, neither phalanx lysis nor digital masses
were found. The long disease-free interval without adjuvant
therapy documented in this case is unusual and is markedly
different from what would be expected from other types of
primary skeletal neoplasia. A long disease-free interval
could have resulted from the so-called “tumor dormancy”
that is well documented in humans and is described in a case
of canine uveal melanoma.14,16-18
Hart hypothesized that malignant cells shed from the primary mass could remain dormant but viable, and that they
could subsequently express their tumorigenic potential as a
consequence of shifts in the balance between the host
immune system and the tumor.17-19 However, the dog in the
authors’ study had a disease-free interval of almost 3.5
years, while the reported case of uveal melanoma metastasized after 1.5 years.14
Primary osseous melanoma reported in humans may
have a good prognosis.20-26 In the dog of this study, the
tumor could have been derived from melanocytes of the
endosteum. However, this hypothesis cannot be substantiated, since melanocytes have not been described in canine
bone (although they have been identified in the endosteum
of reptiles and birds).27,28 Another hypothesis for this
unusual primary location could be the derivation from
pluripotent bone marrow stem cells that are able to differentiate into melanocytic, adipocytic, osteocytic, and chondrocytic lineages.29,30 Moreover, cancer stem cells from
human melanomas (called melanoma cells) have been
demonstrated to differentiate into osteocytes, chondrocytes,
or adipocytes. This further substantiates the hypothesis that
stem cells and phenotypically distinct cancer cells may be
related in some circumstances.29-31 Another possible
hypothesis in this case is that the lesion could have resulted
from an inborn error of migration of melanocytes from the
neural crest into the bone, with subsequent neoplastic transformation.
Conclusion
A primary tibial melanoma was diagnosed in a juvenile dog
based on history and clinical and pathological examinations.
Despite popliteal lymph node invasion, no other distant
metastases developed 43 months after diagnosis. This case
resembles primary osseous melanoma in humans.
Footnotes
a PQ2000S Philips MS; Philips Medical System S.p.A., Monza, Italy
20052
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19. Goldschmidt M, Hendrick M. Tumors of the skin and soft tissues. In:
Meuten D, ed. Tumors in Domestic Animals. 4th ed. Iowa: Ames,
IA, 2002:45-117.
10. Cooley DM, Waters DJ. Skeletal metastasis as the initial clinical
manifestation of metastatic carcinoma in 19 dogs. J Vet Intern Med
1998;12:288-293.
11. Brodey RS, Reid CF, Sauer RM. Metastatic bone neoplasms in the
dogs. J Am Vet Med Assoc 1966;148(1):29-43.
12. Aronsohn MG, Carpenter JL. Distal extremity melanocytic nevi and
malignant melanomas in dogs. J Am Anim Hosp Assoc 1990;26:
605-612.
13. Marino DJ, Matthiesen DT, Stefanacci JD, et al. Evaluation of dogs
with digit masses: 117 cases (1981-1991). J Am Vet Med Assoc
1995;207:726-728.
14. Rovesti GL, Guandalini A, Peiffer R. Suspected latent vertebral
metastasis of uveal melanoma in a dog: a case report. Vet
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15. Henry CJ, Brewer Jr WG, Whitley EM, et al. Canine digital tumors:
a veterinary cooperative oncology group retrospective study of 64
dogs. J Vet Intern Med 2005;19:720-724.
16. Vitetta ES, Tucker TF, Racila E, et al. Tumor dormancy and cell signaling. V. Regrowth of the BCL1 tumor after dormancy is established. Blood 1997;89:4425-4436.
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17. Marches R, Scheuermann RH, Uhr JW. Cancer dormancy: role of
cyclin-dependent kinase inhibitors in induction of cell cycle arrest
mediated via membrane IgM. Cancer Res 1998;58:691-697.
18. Hahnfeldt P, Panygrahy D, Folkman J, et al. Tumor development
under angiogenic signaling: a dynamical theory of tumor growth,
treatment response, and postvascular dormancy. Cancer Res
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19. Hart IR. Perspective: tumor spread—the problems of latency. J
Pathol 1999;187:91-94.
20. Yokoyama R, Mukai K, Hirota T, et al. Primary malignant melanoma
(clear cell sarcoma) of bone: report of a case arising in the ulna.
Cancer 1996;77:2471-2475.
21. Brekke MK, Northcote K, Temple WE. Clear cell sarcoma in the
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1998;88:457-461.
22. Gelczer RK, Wenger DE, Wold LE. Primary clear cell sarcoma of
bone: a unique site of origin. Skeletal Radiol 1999;28:240-243.
23. Inaoka T, Takahashi K, Tandai S, et al. Primary clear cell sarcoma
(malignant melanoma) in the right radius. Skeletal Radiol
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24. Choi JH, Gu MJ, Kim MJ, et al. Primary clear cell sarcoma of bone.
Skeletal Radiol 2003;32:598-602.
25. Hersekli MA, Ozkoc G, Bircan S, et al. Primary clear cell sarcoma
of rib. Skeletal Radiol 2005;34:167-170.
26. Barnes DE, Welling DB, Lucas JG. Melanoma of the petrous apex of
temporal bone. Ann Otol Rhinol Laryngol 1997;106:519-521.
27. Hirano S. Observation on pigment granules in the bones of silky
fowls. Arch Histol Cytol 1990;53:89-93.
28. Hou L, Takeuchi T. Differentiation of extracutaneous melanocytes in
embryos of the turtle, Trionyx sinensis japonicus. Pigment Cell Res
1991;4:158-162.
29. Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of
adult human mesenchymal stem cells. Science 1999;284:143-147.
30. Grichnik JM, Burch JA, Schulteis RD, et al. Melanoma a tumor
based on a mutant stem cell? J Invest Dermatol 2006;126:142-153.
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with stem cell properties in melanomas. Cancer Res 2005;65:
9328-9337.
Sézary Syndrome in a Cat
Sézary syndrome is an uncommon leukemic variant of cutaneous lymphoma in cats. This cat
had recurrent dermatitis with erythematous, pruritic plaques. Multiple skin imprints and biopsy
samples were obtained over a 6-month period, and histopathological findings were consistent
initially with eosinophilic miliary dermatitis and later with erythema multiforme. One week
before death, Sézary cells were identified in the peripheral blood that expressed cluster of differentiation (CD)3 and CD8 antigens. Massive infiltration of CD3+ lymphocytes was noted in
the skin and multiple internal tissues by histopathological examination. This case demonstrates the difficulty in diagnosing cutaneous lymphoma early in the disease course.
J Am Anim Hosp Assoc 2008;44:144-148.
Casey Wood, DVM
Kelli Almes, DVM
Mary Bagladi-Swanson, DVM,
Diplomate ACVD
Brad Debey, DVM, PhD,
Diplomate ACVP
Gordon Andrews, DVM, PhD,
Diplomate ACVP
Jerome Nietfeld, DVM, PhD,
Diplomate ACVP
Melinda Wilkerson, DVM, PhD,
Diplomate ACVP
C
Sézary syndrome is a rare, end-stage leukemic variant of cutaneous T cell
lymphoma (CTCL) and is characterized by the presence of small to large
(8 to 20 µm) lymphocytes with cerebriform or convoluted nuclei (Sézary
cells) in the peripheral blood in addition to erythematous skin lesions and
peripheral lymphadenomegaly.1-4 Diagnosis of CTCL may be difficult,
and the condition may mimic more common pruritic, exfoliative skin
lesions. Multiple cutaneous biopsy samples may be necessary to obtain a
definitive diagnosis.4
The cause of CTCL is unknown in cats. It has been reported, however, that feline leukemia virus (FeLV) could be isolated from tumor
deoxyribonucleic acid (DNA) in a cat with cutaneous lymphoma while
circulating antigen to FeLV was not detected.5 Humans with chronic
atopic dermatitis may have an increased risk for developing CTCL, leading to speculation that chronic antigenic stimulation can lead to the development of CTCL, although the antigen in question is unknown.4,6
The purpose of this paper is to describe a feline case of Sézary syndrome that mimicked other clinical conditions, including eosinophilic
miliary dermatitis and erythema multiforme, until thoroughly investigated postmortem.
Introduction
A 15-year-old, female spayed, domestic shorthair cat was presented for a
recent onset of pruritic, crusty miliary dermatitis that occurred at multiple sites including the neck, dorsum, and inner thighs. Cytological examination of skin imprints revealed many degenerate neutrophils containing
bacterial cocci. Additional skin scrapings for mites and a Wood’s lamp
test for dermatophytes were negative. The cat was discharged on
Clavamox (amoxicillin and clavulanate potassium, 62.5 mg per os [PO]
q 12 hours for 2 weeks) for the bacterial pyoderma.
Two months later, the cat was assessed by a board-certified veterinary
dermatologist and was clinically described to have multifocal areas of
erythema, alopecia, and crusting on the dorsum along with erythema, erosion, and excoriations on the medial thighs and paronychia. Increased
numbers of neutrophils and eosinophils with few round cells were evident
Case Report
From the Departments of
Diagnostic Medicine/Pathobiology
(Wood, Almes, Debey, Andrews,
Nietfeld, Wilkerson) and
Clinical Sciences (Bagladi-Swanson),
College of Veterinary Medicine,
Kansas State University,
1800 Denison Avenue,
Manhattan, Kansas 66506-5705.
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JOURNAL of the American Animal Hospital Association
May/June 2008, Vol. 44
Figure 1—Skin imprint from dorsum; cat. Numerous
eosinophils and a round cell resembling a lymphocyte (Dip
stain, bar=10 µm).
on cytological examination of skin imprints, with
eosinophils predominating [Figure 1]. Staining the preparations with a modified Wright’s staina rather than Dip Stainb
more clearly revealed the round cells as a mixture of poorly granulated mast cells and lymphocytes. A combined
enzyme-linked immunosorbent assay (ELISA) for FeLV
and feline immunodeficiency virus (FIV) was performed on
whole blood and determined to be negative.c The results of
a complete blood count (CBC) and serum biochemical panels performed were within reference intervals. A culture on
hair samples for dermatophytes was performed and exhibited no growth. Streptococcus spp. (beta hemolytic) and
Staphylococcus aureus were isolated from a skin swab.
Because of the antibiotic sensitivity results, the presence of
secondary pyoderma, and possible gastrointestinal irritation
from Clavamox, the antibiotic was switched to clindamycin
(25 mg PO q 12 hours). To help with the intense pruritus,
clemastine (1.34 mg; half tablet PO q 12 hours) was also
initiated. Histopathological examinations of skin samples
taken from the trunk and thigh revealed multifocal, erosive,
suppurative dermatitis with bacterial colonies, epidermal
necrosis, and mast cell infiltrate—consistent with hypersensitivity or miliary dermatitis with secondary pyoderma.
One month later, the cat’s skin condition had not
resolved, despite the continued administration of clindamycin. Concern about the possibility of cutaneous lymphoma as the cat’s underlying problem led to the collection
of a second set of skin biopsy samples, which revealed a
similar histological diagnosis. Complete blood count and
serum biochemical panels were repeated with no abnormal
results noted. As an adjunctive treatment for the intense pruritus, the cat received an injection of 15 mg of Depo Medrol
(methylprednisolone acetate, 20 mg/mL) subcutaneously,
which resulted in slight improvement of the skin lesions for
about 7 to 10 days. Because food allergies can cause cutaneous manifestations of a hypersensitivity response, the cat
Sézary Syndrome in a Cat
145
was started on a food trial using Innovative Veterinary
Diets,d which also was believed to result in mild clinical
improvement for a short time.
Four months after the initial presentation, and despite
being on a food trial, the cat’s dermatitis worsened. It
involved most of the skin of the dorsum and ventrum, leading to almost complete hair loss over the ventrum, inner
thighs, and forelimbs. Patchy alopecia was present over the
dorsum. Skin-punch biopsy samples were collected and
revealed continued presence of eosinophilic and mastocytic
dermatitis. Evidence of individual necrotic keratinocytes
within all layers of the epidermis and follicular epidermis
was suggestive of erythema multiforme [Figure 2].
Lymphocytic infiltrates were also evident in the epidermis
and follicular epidermis [Figure 2]. As a result of this diagnosis and the concern of clindamycin-induced erythema
multiforme, the treatment was switched to enrofloxacin
Figure 2—Skin; cat. Apoptotic keratinocytes (short arrows)
and lymphocytes (long arrows) within the rete pegs of the
epidermis (Hematoxylin and eosin stain, bar=70 µm).
(22.7 mg; one tablet PO q 24 hours for 14 days) and a daily
injection of dexamethasone sodium phosphate (1 mg) subcutaneously for 1 week, followed by tapered doses at every
3-day intervals. The cat responded well to the treatment
within 2 weeks. By 5 months after the initial visit, the
majority of the skin lesions had resolved, hair had regrown,
and pruritus had decreased. A few crusty lesions remained,
principally around the neck and head. Over the next several
months, the cat was treated periodically with antibiotics previously mentioned for recurrent pyoderma. Oral dexamethasone (1 mg q 3 days) was administered for
intermittent pruritus.
Ten months following the initial examination, the cat’s
general condition deteriorated markedly. Physical examination revealed severe, generalized, moist erythematous dermatitis; dehydration; and slight bilateral, popliteal
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May/June 2008, Vol. 44
lymphadenomegaly. Cytological assessment of skin
imprints revealed numerous round cells that resembled
medium-sized lymphocytes containing abundant,
azurophilic, cytoplasmic granules.
A CBCe showed a leukocytosis (27,700/µL, reference
interval 5500 to 19,500/µL) characterized by a neutrophilia
with a left shift (segmented neutrophils 11,400/µL, reference interval 2500 to 12,500/µL; band neutrophils 5000/µL,
reference interval 0 to 300/µL); lymphocytosis (9700/µL,
reference interval 2000 to 7000/µL); basophilia (300/µL,
reference interval 0 to 100/µL); and normocytic, normochromic anemia (packed cell volume 28%, reference
interval 30% to 45%). Examination of the peripheral blood
film demonstrated toxic changes in neutrophils and
increased numbers of lymphocytes with oval to lobulated
nuclei and azurophilic, cytoplasmic granules [Figure 3A].
Occasional cells had cerebriform nuclei resembling Sézary
The lack of finding CD4+ T lymphocytes in an inflammatory leukogram was unusual and suggested a clonal proliferation of CD8+ T cells, which was confirmed 2 weeks later
with a polymerase chain reaction (PCR) assay for T cell antigen-receptor gene rearrangement of the peripheral blood.
However, this information was not known at the time the
CBC results were reported. The presence of a neutrophilia
with a left shift could be explained by chronic inflammation
of the skin. Lymphocytosis with abnormal granular lymphocytes seen in this cat was consistent with a lymphoproliferative disorder or reactive lymphocytosis.
A serum biochemical profileh was performed and
revealed the following abnormalities: increased urea nitrogen (64 mg/dL, reference interval 17 to 35 mg/dL), hyperglobulinemia (5.9 g/dL, reference interval 2.6 to 4.8 g/dL),
increased alanine transaminase (ALT) activity (184 U/L,
reference interval 27 to 127 U/L), and hyperbilirubinemia
Figure 3A—Venous blood; cat. Granular lymphocyte
(Modified-Wright’s stain, bar=6 µm).
Figure 3B—Venous blood; cat. Sézary cell with a cerebriform nucleus (Modified-Wright’s stain, bar=5 µm).
cells [Figure 3B]. Toxic changes in the neutrophil series
included diffuse cytoplasmic basophilia, Döhle bodies, and
occasional asynchronous nuclear maturation.
Leukocytes in the peripheral blood were immunophenotyped using a previously described method and a panel of
monoclonal antibodies to T lymphocyte subsets (i.e., CD4,
CD8),f B lymphocytes (i.e., CD21),g and monocytes (i.e.,
CD14).g,7 The percentages of leukocytes that expressed CD4,
CD8, CD21, and CD14 of the total population were 1%, 85%,
10%, and 4%, respectively. These findings indicated that
CD8+ T cells contributed to the peripheral lymphocytosis.
(total 2.1 mg/dL, reference interval 0.0 to 0.4 mg/dL). The
azotemia was attributed to decreased glomerular filtration
rate secondary to dehydration. The increased ALT activity
indicated hepatocellular damage, and hyperbilirubinemia
was thought to indicate cholestasis. Hyperglobulinemia was
likely caused by chronic inflammation of the skin.
The cat died 3 days later, before any further clinical
assessment or diagnostics could be completed.
A necropsy was performed, and gross examination
revealed diffuse, 2- to 3-mm, cutaneous papules located
over the dorsum, with a normal distribution of hair.
May/June 2008, Vol. 44
However, on the ventrum and medial surfaces of all four
limbs, hair loss was almost complete and accompanied by a
uniform, thick, serous exudate that varied in appearance
from bright red to yellow. The left prescapular lymph node
was enlarged (1.5 by 1.0 by 1.0 cm). All other organs
appeared grossly normal, including the liver, kidney, and
spleen. Histopathological examination of affected skin
revealed diffuse infiltration of the dermis, adnexa, and epidermis, with a population of neoplastic round cells. The
neoplastic round cells ranged in size from 10 to 20 µm, with
indistinct cell borders and scant, pale, eosinophilic cytoplasm. Nuclei were round, centrally located, and measured
10 to 15 µm with hyperchromatic, coarsely stippled chromatin. Mitotic figures averaged 1 per high-power field (40×
objective). Moderate numbers of mast cells were intermixed
with neoplastic cells in the dermis. Neoplastic cells in the
skin stained positively for CD3i [Figure 4A] and negatively
for CD79aj (not shown). Multifocal areas of epidermal
ulceration, neutrophilic crusting with moderate numbers of
cocci, and follicular casts were also present.
Sézary Syndrome in a Cat
147
Identifying the neoplastic lymphocytes in the skin, left
prescapular lymph node, kidney, liver, and spleen as positive for CD3 (a mature T cell surface marker) and the presence of these neoplastic lymphocytes within the epidermis
led to a diagnosis of epitheliotropic CTCL. Furthermore,
immunophenotyping and PCR assay for antigen-receptor
gene rearrangement of the lymphocytes in the blood subclassified the T cells as a clonal population of CD8+ cells.
To the authors’ knowledge, this is the first case of Sézary
syndrome in a cat in which the Sézary cells were identified
as CD8+ T cells with a clonal rearrangement of the T cell
antigen receptor.
Cutaneous T cell lymphoma in humans is usually characterized by an elevated dermal CD4+/CD8- ratio and the
presence of a T cell clone detected by PCR in tissues and
peripheral blood.8,9 In humans with Sézary syndrome, the
cells are most commonly reported as CD4+ T cells, whereas cases that express CD8 are less common.8 It is possible
that this cat had an unusual form of Sézary syndrome in
Discussion
Figure 4A—Skin of ventrum; cat. Immunohistochemical
staining for CD3 expression on lymphocytes that infiltrate
the dermis and epidermis (Ventana Red detection kit,
Mayer’s hematoxylin counterstain, bar=60 µm).
Figure 4B—Liver; cat. Eosinophils comprise the majority of
infiltrating cells in the sinusoids (Hematoxylin and eosin
stain, bar=70 µm).
The left prescapular lymph node architecture was effaced
by similar neoplastic round cells. Neoplastic round cells and
moderate numbers of eosinophils and plasma cells were also
present within portal areas and surrounding sinusoids of the
liver [Figure 4B]. Neoplastic cells were also found in renal
tubular epithelial cells. The white pulp of the spleen was diffusely infiltrated with similar cell populations. Due to the
positive staining of these neoplastic cells with CD3 and the
negative staining for CD79a, the cat was diagnosed with disseminated epitheliotropic CTCL (also known as mycosis fungoides). These findings, together with identification of Sézary
cells in the blood, supported a diagnosis of Sézary syndrome.
which a proliferation of CD8+ rather than CD4+ lymphocytes was present. However, more cases of Sézary syndrome in cats will need to be immunophenotyped to
determine if the cell type is more commonly CD4+, as it is
in humans.
In this cat, frequent lymphocytes were noticed in the
mixed inflammatory cell population of the skin imprints and
in the epidermis upon histopathological examination of
some skin biopsy samples. However, hypersensitivities to
various antigens can cause nonmalignant accumulation of
lymphocytes in the skin, and early in the course of CTCL,
the infiltrative lymphocytes are usually reactive T cells.10,11
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JOURNAL of the American Animal Hospital Association
Histologically, it can be nearly impossible to differentiate
benign inflammatory skin diseases from early CTCL.12
Erythema multiforme, diagnosed earlier in the disease
course by histopathological examinations of skin biopsy
samples, is also characterized by invasion of the epidermis
by T cells (usually CD8+), leading to keratinocyte apoptosis.13 The earlier diagnosis of erythema multiforme was also
supported by the administration of various antibiotics (clindamycin) that have been associated with the development of
erythema multiforme, and by apparent partial resolution of
most of the skin lesions for a few months after removal of
the suspected offending drug.13,14 It is possible that the
slow progression of disease seen in this case contributed to
the lack of an earlier, more specific diagnosis.
The prominence of eosinophils may be explained by the
presence of T helper 2 (Th2) lymphocyte cytokines (e.g.,
interleukin [IL]-3, IL-4, or IL-5) that stimulate growth and
differentiation of eosinophils.15-17 In humans, Sézary syndrome and hypereosinophilia are associated with increased
Th2 cytokines and are related to the progression of the lymphoma malignancy.16 Rare, paraneoplastic, hypereosinophilic syndromes have been described in horses and dogs
that have concurrent lymphoma; however, cytokine production in these disorders has not been defined.18,19
The cause of sudden death in this cat is unknown. Death
in cats and dogs with CTCL is reported to be most commonly caused by septicemia or metastatic lymphoma.3
Humans with CTCL frequently succumb to fatal opportunistic infections.20
This case report is an example of Sézary syndrome, a rare,
end-stage leukemic form of CTCL. This report is unique in
that it demonstrates CD8+ Sézary cells in a cat.
Conclusion
a Richard Allen Scientific, Kalamazoo, MI 49008
b Volu-Sol, Inc., Salt Lake City, UT 84121
c IDEXX Laboratories, Westbrook, ME 04092
d Royal Canin USA, Inc., St. Charles, MO 63301
e Cell-Dyn 3700; Abbott Laboratories, Abbott Park, IL 60064-3500
f Southern Biotechnology, Birmingham, AL 35260
g Serotec, Raleigh, NC 27604-1699
h Boehringer Mannheim/Hitachi 911, Indianapolis, IN 46250
i Rabbit antihuman; DAKO, Carpintera, CA 93013
Footnotes
Ventana Red detection kit; Ventana Medical Systems, Inc., Tucson, AZ
85755
j HM57; DAKO, Carpintera, CA 93013
The authors acknowledge Drs. Marjorie Arzter, Susan
Nelson, and Laura Garrett for their care of the animal and
their contributions to this case; Dr. Mehrdad Ameri for
immunophenotyping the peripheral blood; Dr. Anne Avery
for the PCR testing; and Cindy Chard-Bergstrom for the
immunohistochemical testing.
Acknowledgments
May/June 2008, Vol. 44
11. Thrall MA, Macy DW, Snyder SP, et al. Cutaneous lymphosarcoma
and leukemia in a dog resembling Sezary syndrome in man. Vet
Pathol 1984;21:182-186.
12. DeBoer DJ, Turrel JW, Moore PF. Mycosis fungoides in a dog:
demonstration of T cell specificity and response to radiotherapy. J
Am Anim Hosp Assoc 1990;26:566-572.
13. Moriello KA. Cutaneous lymphoma and variants. In: Feldman B,
Zinkl J, Jain N, eds. Schalm’s Veterinary Hematology. 5th ed.
Philadelphia: Lippincott Williams & Wilkins, 2000:648-653.
14. Kotz EA, Anderson D, Thiers BH. Cutaneous T cell lymphoma. J
Eur Acad Dermatol Venereol 2003;17:131-137.
15. Tobey JC, Houston DM, Breur GJ, et al. Cutaneous T cell lymphoma
in a cat. J Am Vet Med Assoc 1994;204:606-609.
16. Foon KA, Ghobrial I, Geskin LJ, et al. The non-Hodgkin lymphomas. In: Lichtman MA, Beutler E, Kipps TJ, et al., eds. Williams
Hematology. 7th ed. New York: The McGraw-Hill Companies, Inc.,
2006:1407-1459.
17. Wilkerson MJ, Dolce K, Koopman T, et al. Lineage differentiation of
canine lymphoma/leukemias and aberrant expression of CD molecules. Vet Immunol Immunopathol 2005;106:179-196.
18. Papadavid E, Economidou J, Psarra A, et al. The relevance of
peripheral blood T-helper 1 and 2 cytokine pattern in the evaluation
of patients with mycosis fungoides and Sezary syndrome. Br J
Dermatol 2003;148:709-718.
19. Laetsch B, Haffner AC, Dobbeling U, et al. CD4 + /CD7- T cell frequency and polymerase chain reaction-based clonality assay correlate with stage in cutaneous T cell lymphomas. J Invest Dermatol
2000;114:107-111.
10. Duvic M, Edelson R. Cutaneous T cell lymphoma. J Am Acad
Dermatol 2004;51:S43-S45.
11. Gilbert S, Affolter VK, Gross TL, et al. Clinical, morphological and
immunohistochemical characterization of cutaneous lymphocytosis
in 23 cats. Vet Dermatol 2004;15:3-12.
12. Vonderheid EC. On the diagnosis of erythrodermic cutaneous T-cell
lymphoma. J Cutan Pathol 2006;33(Suppl 1):27-42.
13. Scott DW, Miller W. Erythema multiforme in dogs and cats: literature review and case material from the Cornell University College of
Veterinary Medicine (1988-1996). Vet Dermatol 1999;10:297-309.
14. Affolter VK, Von Tscharner C. Cutaneous drug reactions: a retrospective study of histopathological changes and their correlation with
the clinical disease. Vet Dermatol 1993;4:79-86.
15. Borish L, Dishuck J, Cox L, et al. Sezary syndrome with elevated
serum IgE and hypereosinophilia: role of dysregulated cytokine production. J Allergy Clin Immunol 1993;92:123-131.
16. Saed G, Fivenson DP, Naidu Y, et al. Mycosis fungoides exhibits a
Th1-type cell-mediated cytokine profile whereas Sezary syndrome
expresses a Th2-type profile. J Invest Dermatol 1994;103:29-33.
17. Suchin KR, Cassin M, Gottleib SL, et al. Increased interleukin 5
production in eosinophilic Sezary syndrome: regulation by interferon
alpha and interleukin 12. J Am Acad Dermatol 2001;44:28-32.
18. La Perle KM, Piercy RJ, Long JF, et al. Multisystemic, eosinophilic,
epitheliotropic disease with intestinal lymphosarcoma in a horse. Vet
Pathol 1998;35:144-146.
19. Marchetti V, Benetti C, Citi S, et al. Paraneoplastic hypereosinophilia in a dog with intestinal T cell lymphoma. Vet Clin Pathol
2005;34:259-263.
20. Lorincz AL. Cutaneous T-cell lymphoma (mycosis fungoides).
Lancet 1996;347:871-876.
References
Primary Tracheal Collapse in a Cat
A 7-year-old, neutered male, domestic shorthair cat was presented for severe inspiratory
dyspnea of 2 to 3 days’ duration. Radiography and tracheobronchoscopy confirmed the diagnosis of primary extrathoracic tracheal collapse. The cat was treated with oxygen, dexamethasone, and terbutaline, but no improvement was seen. Surgical correction was performed
using nine prosthetic tracheal ring implants. Clinical signs improved after surgery, and the cat
continued to do well 11 months after surgery, despite development of unilateral laryngeal
paralysis. J Am Anim Hosp Assoc 2008;44:149-153.
Holly L. Mims, DVM
Robert B. Hancock, DVM,
MS, Diplomate ACVS
Michael S. Leib, DVM, MS,
Diplomate ACVIM
Don R. Waldron, DVM, MS,
Diplomate ACVS,
Diplomate ABVP
C
From the Department of
Small Animal Clinical Sciences,
Virginia-Maryland Regional College
of Veterinary Medicine,
Virginia Tech, Blacksburg, Virginia 24061.
Doctor Mims’ current address is
Veterinary Specialty Hospital
of the Carolinas,
6405 Tryon Road, Suite 100,
Cary, North Carolina 27518.
Doctor Hancock’s current address is
Louisiana Veterinary Referral Center,
2611 Florida Street,
Mandeville, Louisiana 70448.
JOURNAL of the American Animal Hospital Association
A 7-year-old, neutered male, domestic shorthair cat was presented for
persistent dyspnea of 2 to 3 days’ duration. Abnormalities on physical
examination at presentation included increased inspiratory effort and
tachypnea. A cough was easily elicited on palpation of the extrathoracic
trachea. No abnormalities were noted on auscultation of the heart and
lungs. Thoracic radiographs indicated narrowing of the tracheal lumen at
the junction of the thoracic inlet on inspiration, with no evidence of extraluminal compression [Figure 1]. The cat was placed in a 40% oxygen
cage and given dexamethasone (0.2 mg/kg intravenously [IV]).
Hematological and serum biochemical analyses performed the next
day revealed a mature neutrophilia (15.326 × 10³/µL, reference range 1.1
to 10.4 × 10³/µL), lymphopenia (0.316 × 10³/µL, reference range 1.5 to 7
× 10³/µL), eosinopenia (0 × 10³/µL, reference range 0.037 to 0.914 ×
10³/µL), hyperglycemia (223 mg/dL, reference range 59 to 124 mg/dL),
hyperproteinemia (8.3 g/dL, reference range 6.5 to 7.7 g/dL), hyperglobulinemia (4.9 g/dL, reference range 2.5 to 4.7 g/dL), and hypocholesterolemia (76 mg/dL, reference range 101 to 409 mg/dL). The
hematological changes and hyperglycemia were attributed to stress. The
mild elevation in globulins and the hypocholesterolemia were considered
incidental findings. Results of feline immunodeficiency virus and feline
leukemia virus tests were negative.
Anesthesia was induced with propofol (6 mg/kg IV) and maintained
with isoflurane. Laryngeal examination performed before intubation
revealed no evidence of pharyngeal or laryngeal masses. Arytenoid
abduction was within normal limits. The nasopharynx was normal on
retroflex examination. An endotracheal tube was then placed to maintain
general anesthesia. Tracheobronchoscopy revealed a normal tracheal
lumen for the first 20 cm of the trachea (measured from the upper canine
teeth), with collapse along the dorsal membrane thereafter [Figure 2].
The distal luminal diameter was decreased by approximately 75% and
was classified as a grade III collapse.1 Beyond the thoracic inlet, the
diameter of the trachea appeared within normal limits, and the main-stem
bronchi were identified. Esophagoscopy revealed no evidence of extraluminal compression, suggesting a diagnosis of tracheal collapse.
Over the following 2 days, the cat remained in an oxygen (40%) cage,
and dexamethasone treatment was continued. Diazepam (0.37 mg/kg IV)
and butorphanol (0.2 mg/kg IV) were administered as needed for
Case Report
149
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JOURNAL of the American Animal Hospital Association
Figure 1—Lateral thoracic radiograph of a 7-year-old cat
with severe inspiratory dyspnea. The film was taken upon
inspiration, evidenced by the pulmonary cupula extending
beyond the first rib. The entire tracheal lumen is narrowed,
which is more severe in the cervical region. Dynamic cervical tracheal collapse was confirmed with bronchoscopy.
Figure 2—Bronchoscopic view of the trachea, demonstrating reduction in the dorsoventral dimension of the airway in
the cervical trachea and collapse of the dorsal membrane.
increased respiratory difficulty or increased anxiety. An oral
suspension of terbutaline (0.03 mg/kg per os [PO] q 8
hours) was started on day 3 of hospitalization in an attempt
to induce bronchodilation. The cat’s clinical signs continued
to worsen despite medical management, and the owners
elected surgery on day 4.
The cat was anesthetized using the previously described
protocol and was prepared for surgery. The skin and subcutaneous tissues along the ventral cervical midline were
incised from the larynx to the manubrium. The sternohyoid
and sternocephalicus muscles were separated along their
May/June 2008, Vol. 44
midline to expose the cervical trachea. The recurrent laryngeal nerves were identified, protected, and retracted away
from the trachea. The peritracheal tissues were dissected,
creating a tunnel immediately around the specific areas of
the trachea that were to be fitted with prosthetic rings. Nine
prosthetic rings (each 1 cm wide) were placed around the
trachea about 5 to 8 mm apart. The rings had been constructed from 3-mL syringe cases and fenestrated in four
places to allow suture placement. The first tracheal prosthesis was placed 1 cm distal to the larynx, and the last was
placed at the thoracic inlet. A curved hemostat was used to
guide and position each ring around the trachea. The open
end in each ring was positioned on the ventral aspect of the
trachea, and the rings were then secured ventrally, laterally,
and dorsally with 4-0 polypropylene sutures. Sutures were
directed around rather than through the cartilages, with at
least one of the sutures for each ring engaging the trachealis
muscle. Cranial traction on the prosthesis allowed one ring
to be placed at the thoracic inlet. After each ring was placed,
the endotracheal tube was manipulated to ensure it had not
been sutured to the trachea. Specimens for bacterial culture
were obtained from several of the prosthetic rings before
closure.
The sternohyoid and sternocephalicus muscles were
apposed with simple continuous sutures of 3-0 polydioxanone (PDS), and the subcutaneous tissues were closed in
the same fashion. The dermis was closed with a continuous
intradermal pattern using 4-0 PDS. Cruciate sutures were
then placed using 3-0 nylon.
Tracheobronchoscopy was performed immediately after
surgery. The trachea was erythematous, with a small amount
of blood visible within the lumen. The scope was advanced
13 to 15 cm caudal to the nares. Narrowing of the tracheal
lumen was minimal as far distally as could be visualized.
The suture material used to secure the prosthetic rings could
be seen within the lumen. The bronchi appeared normal,
with no evidence of collapse. A 25-µg fentanyl patch was
placed postoperatively for analgesia.
The cat recovered well from anesthesia and surgery. Oral
amoxicillin-clavulanate (12 mg/kg q 12 hours) was administered for 2 weeks after surgery. Bacterial cultures of tracheal specimens taken at surgery were negative. Thoracic
radiographs taken before discharge showed a 100% increase
in the diameter of the tracheal lumen compared with the size
of the lumen on radiographs taken at initial presentation
[Figure 3]. By the time of discharge 7 days after surgery, the
clinical signs of tracheal collapse had markedly improved.
Two months later, the owners reported the cat was doing
well with minimal coughing.
The cat returned 1 month after surgery for reevaluation.
The owners reported no respiratory difficulty, coughing,
heat intolerance, or exercise intolerance since the surgery,
but they had noticed a change in voice. A laryngeal examination performed under light sedation revealed right-sided
laryngeal paralysis. This complication was attributed to
damage to the recurrent laryngeal nerve that was likely secondary to retraction during surgery, despite the authors’
May/June 2008, Vol. 44
Figure 3—Lateral thoracic radiograph obtained several
days after surgery. Tracheal luminal diameter is increased
100% compared to that seen on thoracic radiographs
obtained before surgery.
attempts to protect the nerve. During tracheobronchoscopy,
suture material could be seen intermittently in the tracheal
lumen from 9.5 cm caudal to the upper canines to the thoracic inlet [Figure 4]. Redundant dorsal membrane was evidenced in the distal trachea, but overall, the tracheal
diameter appeared normal.
Figure 4—Bronchoscopic view of the trachea 11 months
after surgical correction of the collapsed region. Note the
blue suture material within the tracheal lumen.
Tracheal collapse is described as a dorsoventral flattening of
the tracheal rings with concurrent laxity of the dorsal tracheal membrane.1-5 It is diagnosed most commonly in middle-aged toy and small-breed dogs, but it has also been
Discussion
Primary Tracheal Collapse in a Cat
151
reported rarely in cats, calves, pigs, horses, and goats.6
Clinical signs are often exacerbated by heat, excitement,
and eating or drinking. A history of chronic coughing, exercise intolerance, and dyspnea is common in canine patients;
coughing is less common in feline patients. Feline cases are
typically secondary to intra- or extraluminal obstruction
caused by tumors, trauma, or congenital abnormalities.7,8
Definitive diagnosis of tracheal collapse requires imaging studies and/or tracheobronchoscopy. Plain radiographs
have been shown to be diagnostic in 59% of canine cases.2,8
Lateral views of the thorax should be obtained during both
inspiration and expiration. Inspiratory films best demonstrate collapse of the cervical trachea, while expiratory films
demonstrate collapse of the main-stem bronchi or intrathoracic trachea.1,2 Other noninvasive techniques, such as fluoroscopy and ultrasonography, can provide diagnostic
support when thoracic radiographs alone are insufficient.3
Fluoroscopy can be beneficial in identifying collapse of the
main-stem bronchi, which is not often evident on thoracic
radiographs.1 Fluoroscopy is also a dynamic study that is
performed in a conscious animal and allows identification
of tracheal collapse during active coughing.8 Regardless,
tracheobronchoscopy remains the most sensitive and specific diagnostic method, and it is the method of choice for
visualizing the dorsal tracheal ligament and tracheal
mucosa.2,3 In addition, the tracheal mucosa and secretions
can be evaluated, and samples for cytology and bacteriology can be collected. The animal should be lightly anesthetized before tracheoscopy to allow evaluation of
swallowing reflexes and laryngeal function.1
Although the inciting cause of tracheal collapse has not
yet been determined, it is known that this condition is associated with a defect in the tracheal cartilage that results in
loss of rigidity.2 In some dogs with tracheal collapse, the
tracheal cartilage is hypocellular with less chondroitin sulfate and calcium than normal tracheal cartilage.1 It has been
postulated that both the abnormal cartilage and the aging
process play a role.9
Tracheal collapse can be managed medically or surgically, but neither treatment is curative. Medical management
most often includes some combination of weight loss,
antibiotics, antitussives, bronchodilators, antiinflammatories, and treatment of the underlying cause (if identified).1
Medical treatment of an animal with acute tracheal collapse
and dyspnea should include oxygen.
Specimens collected from the trachea for cytology and
culture can be used to guide antibiotic therapy and to diagnose bacterial infection or allergic tracheitis that could be
the initiating cause of tracheal collapse. Positive tracheal
cultures have not been associated with cytological evidence
of infection or inflammation, which suggests that antimicrobial therapy is not necessarily indicated in the treatment
of tracheal collapse.10 Organisms other than Bordetella
bronchiseptica may be normal tracheal flora.
Antitussives are commonly recommended in dogs to
reduce irritation and epithelial damage caused by chronic
coughing. Coughing perpetuates collapse by initiating
152
JOURNAL of the American Animal Hospital Association
inflammation, which increases mucous production and
decreases mucociliary clearance.1 Bronchodilator treatment
is controversial and appears to improve large-airway collapse by minimizing small-airway obstruction and thereby
reducing intrathoracic pressure.8 Terbutaline was added to
the treatment regimen of this cat to reduce intrathoracic
pressure and potentially prevent large-airway collapse
despite absence of small-airway disease.
Surgical treatment is recommended when the animal is
not responding to medical therapy or when the quality of
life has diminished.1 Many surgical options for tracheal collapse have been described, including tracheal ring chondrotomy, plication of the dorsal tracheal membrane, tracheal
resection and anastomosis, and intra- or extraluminal tracheal prostheses.5,11-13 Most of these techniques have not
been successful, but extraluminal prostheses (spiral or total
ring) have had the most success.11 Some surgeons prefer
spiral prostheses over complete-ring prosthetics because of
reports of improved flexibility and support of the trachea, as
well as uniform contact of the spiral prostheses and the trachea.1,13 Also, in a ventral approach through the cervical
midline, the spiral prosthesis can be placed further into the
thorax than the complete-ring prosthesis.14 Spiral prostheses
have been associated with tracheal necrosis due to extensive
soft-tissue dissection, but newer surgical approaches have
been described to help avoid this complication.1,13
Placement of prosthetic rings generally reduces clinical
signs by 75% to 85%, with the most common postoperative
complications being laryngeal paralysis, coughing, and dyspnea.1 Laryngeal paralysis is most often caused by trauma to
the recurrent laryngeal nerve during surgery.15 Tracheal
necrosis can occur in the days after surgery if the tracheal
blood supply is damaged during the procedure.1
Since 1974, six cases of intratracheal obstruction or neoplasia have been reported in cats, but only two of these
cases had evidence of secondary tracheal collapse.16-20 In
these two cases, tracheal collapse was cranial to the thoracic
inlet and caudal to an intraluminal obstructing lesion.
Squamous metaplasia was the primary cause of collapse in
one of these cats, and a congenital abnormality with granulomatous changes was the primary cause of collapse in the
other.20 In 1991, a case of tracheal collapse in a cat was
reported secondary to suspected trauma, and surgical correction using a spiral-cut prosthesis was successful.7 The
authors are unaware of any previous reports of successful
surgical correction of primary tracheal collapse in a cat.
The signalment in this case was atypical, because primary tracheal collapse is not common in cats, and this cat
had no history of prior or progressive clinical signs. No
signs of an inciting cause were identified on radiography,
laryngeal examination, tracheobronchoscopy, or esophagoscopy. No gallop rhythm or heart murmur was auscultated in this cat, although echocardiography would be
required to exclude concurrent heart disease. The acute
onset of signs after being outdoors is more consistent with
trauma, allergies, or toxins, although none could be identified. It is plausible that heat stress could have contributed to
May/June 2008, Vol. 44
the acute onset and exacerbated the weakened dorsal tracheal membrane. Multiple radiographic images of the thorax
were obtained to exclude other disease processes. Ideally,
both inspiratory and expiratory thoracic radiographs should
have been obtained, but they were not in this case because of
the cat’s respiratory distress upon initial presentation. The
diagnosis in this case was based on tracheobronchoscopy,
which revealed the redundant dorsal tracheal membrane that
is consistent with tracheal collapse in small-breed dogs.
The cat’s condition continued to worsen in the hospital
with medical management alone, and increasingly frequent
sedation was required to decrease anxiety and ease respiratory effort. Medical management with corticosteroids was
ultimately insufficient, and the decision for surgery was a
final attempt at treatment. The surgical approach and procedure were identical to those reported for repair of collapsing
trachea in dogs, and they effectively reduced clinical signs
in this cat. The surgeon chose individual, polypropylene
rings as prostheses. Intraluminal stents were not used,
because the surgeons were not experienced using this new
modality at the time. In addition, intraluminal stenting was
associated with many complications and was not a widely
accepted procedure at the time.
Primary tracheal collapse is diagnosed most commonly in
toy and small-breed dogs, but cats can also be affected. A
history of exercise intolerance and dyspnea in feline
patients should prompt airway evaluation via radiography,
fluoroscopy, or tracheobronchoscopy. Although most
reported cases of tracheal collapse in cats have been secondary to other disease processes such as neoplasia, primary
tracheal collapse should also be considered. Surgery using
extraluminal prostheses seems to be a viable option for correction of primary tracheal collapse in cats.
Conclusion
The authors thank TC Coffman and Drs. Michelle Fabiani
and Derek Burney for their contributions.
Acknowledgments
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