DIAGNOSIS AND TREATMENT OF A DERMAL
MALIGNANT MELANOMA IN AN AFRICAN LION
(PANTHERA LEO)
Author(s): James C. Steeil , D.V.M., Juergen Schumacher , Dr. med. vet., Dipl.
A.C.Z.M., Dipl. E.C.Z.M. (Herpetology), Katherine Baine , D.V.M., Edward C.
Ramsay , D.V.M., Dipl. A.C.Z.M, Patricia Sura , D.V.M., M.S., Dipl. A.C.V.S.,
Rebecca Hodshon , D.V.M., Dipl. A.C.V.S., Robert L. Donnell , D.V.M., PhD,
Dipl. A.C.V.P., and Nathan D. Lee , D.V.M., Dipl. A.C.V.R.
Source: Journal of Zoo and Wildlife Medicine, 44(3):721-727. 2013.
Published By: American Association of Zoo Veterinarians
DOI: http://dx.doi.org/10.1638/2013-0023R2.1
URL: http://www.bioone.org/doi/full/10.1638/2013-0023R2.1
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Journal of Zoo and Wildlife Medicine 44(3): 721–727, 2013
Copyright 2013 by American Association of Zoo Veterinarians
DIAGNOSIS AND TREATMENT OF A DERMAL MALIGNANT
MELANOMA IN AN AFRICAN LION (PANTHERA LEO)
James C. Steeil, D.V.M., Juergen Schumacher, Dr. med. vet., Dipl. A.C.Z.M., Dipl. E.C.Z.M.
(Herpetology), Katherine Baine, D.V.M., Edward C. Ramsay, D.V.M., Dipl. A.C.Z.M, Patricia Sura,
D.V.M., M.S., Dipl. A.C.V.S., Rebecca Hodshon, D.V.M., Dipl. A.C.V.S., Robert L. Donnell, D.V.M.,
PhD, Dipl. A.C.V.P., and Nathan D. Lee, D.V.M., Dipl. A.C.V.R.
Abstract: A 13-yr-old intact male African lion (Panthera leo) presented with a 4-mo history of left maxillary lip
swelling. On physical examination, a 10-cm-diameter, ulcerated, round, firm, and pigmented mass at the level of
the left maxillary canine tooth was noticed. All other organ systems examined were within normal limits. Multiple
biopsies of the mass were collected and fixed in 10% neutral buffered formalin. Histopathologic evaluation of the
biopsies revealed a malignant dermal melanoma. Hematologic and plasma biochemical parameters were within
normal reference ranges. Thoracic radiographs taken 3 days following initial presentation showed no evidence of
metastasis of the tumor. Computed tomography of the skull and neck was performed to evaluate local tumor
invasion and to plan for hypofractionated radiation therapy. Therapy included four weekly treatments of 8 gray
external-beam hypofractionated radiation and four bimonthly immunotherapy treatments. Following this
treatment regime, the tumor size was reduced by 50%, and surgical excision was performed. No major side
effects associated with radiation or immunotherapy were seen. Six months after diagnosis, hematologic and
plasma biochemical parameters were within normal limits, thoracic radiographs showed no evidence of
metastasis, and the lion showed no clinical signs of disease. The lion will continue to receive immunotherapy
every 6 mo for the rest of its life. To the authors’ knowledge, this is the first report of a successful treatment of a
malignant dermal melanoma with external-beam hypofractionated radiation, immunotherapy, and surgical
excision in an African lion.
Key words: African lion, immunotherapy, melanoma, Panthera leo, radiation therapy.
INTRODUCTION
Melanomas are ‘‘round cell imposter’’7 tumors
of melanocytes or melanoblasts19 and have been
reported in domestic animals to be either benign
or malignant. In domestic animals, malignancy is
determined by tissue site, mitotic index, tumor
size, lymphatic invasion, and breed.19 In domestic
cats, melanomas have been reported to affect
ocular, dermal, or oral tissues.12,13,15 Whereas
ocular and oral melanomas have been shown to
be highly aggressive, dermal melanomas can be
either malignant or benign.19 Reports in the
literature of malignant melanomas in exotic felids
are scant.4,17
The treatment of choice for patients with
melanoma is surgical excision of the mass with
at least 2-cm margins.20 Because of the aggressive
nature of melanomas, thoracic radiographs, routine hematologic blood tests (complete blood
From the Departments of Small Animal Clinical
Sciences (Steeil, Schumacher, Baine, Ramsay, Sura, Hodshon, Lee), and Biomedical and Diagnostic Sciences
(Donnell), College of Veterinary Medicine, The University
of Tennessee, 2407 River Drive, Knoxville, Tennessee
37996, USA. Correspondence should be directed to Dr.
Steeil ([email protected]).
count and chemistry panels), and aspiration of
regional lymph nodes are recommended to determine if metastatic disease is present. External
beam radiation therapy can be used successfully
to control local disease as a primary or adjunctive
treatment for malignant melanomas,5,6,16 but chemotherapy has been shown to be of little benefit.19
Recently, immunotherapy has been reported as an
effective treatment of micrometastatic disease
associated with malignant melanomas after surgical excision of the primary mass in dogs9; it
increased disease-free intervals and median survival times.3
CASE REPORT
A 13-yr-old, intact male African lion (Panthera
leo) presented with a 4-mo history of facial
swelling of the left maxillary lip at the level of
the left upper canine tooth. Four months prior to
evaluation, a tick was seen on the left lower eyelid,
and the lion had severely scratched the left side of
its face in attempts to remove the tick. During this
time, the lion had been empirically treated with
amoxicillin/clavulanic acid (Clavamox, Pfizer,
New York, New York 10017, USA; 10 mg/kg
p.o. b.i.d. for 14 days) for a suspected abscess
because of the excoriation incident. Despite
721
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JOURNAL OF ZOO AND WILDLIFE MEDICINE
antibiotic therapy, the swelling continued to
slowly enlarge until the time of examination.
The lion was immobilized with medetomidine
(Wildlife Pharmaceuticals, Windsor, Colorado
80550, USA; 27 mcg/kg i.m.), midazolam (NovaPlus, Hospira, Lake Forest, Illinois 60045, USA;
0.1 mg/kg i.m.), and ketamine (Ketaset, Fort
Dodge Animal Health, Fort Dodge, Iowa 50501,
USA; 3 mg/kg i.m.). This protocol was used for
all subsequent immobilizations. Physical examination revealed a 10-cm-diameter, ulcerated,
round, firm, and darkly pigmented mass along
the left maxillary cheek. The mass bled easily and
was suspected to be a neoplastic mass of uncertain histologic type. The mass was infused with a
2% lidocaine solution (Hospira, 1 mg/kg) and
three 6-mm punch biopsies were obtained from
various areas of the mass. Biopsy specimens were
fixed in 10% neutral buffered formalin, and
biopsy sites were closed with polydioxanone
(PDS, Ethicon, Somerville, New Jersey 08876,
USA) in a simple interrupted pattern. All other
physical examination findings were within normal
limits. A blood sample was collected from the
saphenous vein for determination of hematologic
and plasma biochemical parameters. At the end of
the procedure, the effects of medetomidine were
reversed with atipamezole (Antisedan, Pfizer;
0.13 mg/kg i.m.).
Hematology and plasma biochemistry panels
were within normal limits. Histopathology of
biopsy specimens of the mass showed that the
deep dermal, subcutaneous, and muscular tissue
architecture was variably disrupted to effaced by a
highly pleomorphic population of heavily to
minimally pigmented cells arranged in sheets,
streams, and islands (Fig. 1A). These cells had
marked anisocytosis and anisokaryosis. Mitotic
figures averaged one per 10 high-power (340)
fields. Neoplastic cells were also present within
multiple blood vessels (Fig. 1B). A diagnosis of a
malignant melanoma was made based on the size
of the mass and vascular invasion present on
histopathology.
Three days after initial presentation, the lion
was immobilized for further diagnostics, including computed tomography (CT) of the head and
neck, thoracic radiographs, and possible surgical
excision of the mass. At this time, the mass
measured 4.5 cm (medial to lateral) 3 10 cm
(rostral to caudal) 3 10 cm (dorsal to ventral).
Anesthesia was induced with a combination of
medetomidine, midazolam, and ketamine, as
previously described. Following induction of
anesthesia, the trachea was intubated with a 20-
mm cuffed endotracheal tube, and anesthesia was
maintained with isoflurane (IsoFlo, Abbott Animal Health, North Chicago, Illinois 60064, USA;
1–4%) in 100% oxygen for the remainder of the
procedure. An 18-gauge, 1.25-in intravenous
catheter was placed in the medial saphenous vein,
and Normosol R (Hospira) was administered i.v.
at 10 ml/kg/hr throughout the anesthetic event.
Iodinated contrast was administered during the
CT scan (Optiray, Covidien Pharmaceuticals,
Hazelwood, Missouri 63042, USA; 100 ml i.v.
once).
Thoracic radiographs showed moderate diffuse
nonstructured interstitial opacities throughout
the lung and mild bronchial mineralization consistent with age-related changes. No evidence of
metastatic disease was present. CT was performed
using a 40-slice helical CT scanner (Philips
Brilliance-40, Philips International B.V., Amsterdam, The Netherlands) on the head and neck of
the lion to evaluate tumor margins and regional
lymph nodes and aid in radiation planning. Fourmillimeter transverse images were acquired from
the most rostral portion of the head to the cranial
aspect of the second thoracic vertebra. There was
a mixed hyper- and medium attenuating mass
within the left labium extending from approximately the level of the incisor teeth caudally to the
level of the third maxillary premolar tooth (Fig.
2). The mass extended dorsally to the junction of
the labium into the adherent maxillary soft
tissues. There was no associated bone abnormality. On postcontrast images, there was heterogeneous enhancement of the left labial mass. CT
assessment of regional lymph nodes was somewhat compromised by the animal’s relatively lean
conformation, but no significant lymphadenopathy was identified. At the time, lymph node
aspiration was not pursued given the findings on
CT scan. Given the size and location of the mass,
surgical removal and primary closure were determined to be impossible at that time. In an attempt
to reduce tumor size and facilitate surgical
excision, weekly external-beam hypofractionated
radiation therapy was administered for four
treatments. At the time, chemotherapy was discussed, but because of the short and minimal
response of domestic animal melanomas to chemotherapy and the owners’ concern for adverse
side effects to the drugs, this treatment modality
was not pursued in this case. Radiation therapy
was also accompanied twice by immunotherapy
with a melanoma vaccine (Oncept, Merial, Duluth, Georgia 30096, USA; 1 ml administered
STEEIL ET AL.—MELANOMA IN A LION
723
Figure 2. Transverse CT image of a male African
lion (P. leo) demonstrating a mixed hyper- and medium
attenuating mass (white arrow) within the left labium
extending from approximately the level of the incisor
teeth caudally to the level of the third maxillary
premolar tooth.
Figure 1. Photomicrographs of a dermal melanoma
in a 13-yr-old African lion (P. leo). A. Tissue architecture is variably disrupted to effaced by a highly
pleomorphic population of heavily to minimally pigmented cells arranged in sheets, streams, and islands
(340, H&E). The cells have marked anisocytosis and
anisokaryosis with single to multiple nuclei (white
arrows). B. Neoplastic cells are seen within blood
vessels (white arrows).
transdermally into the medial thigh every 2 wk for
four treatments).
Hypofractioned radiation therapy consisted of
8 gray (Gy) once a week for 4 wk. The radiation
protocol was chosen in part based on a report of
the treatment of domestic cats with oral melanomas with 8 Gy weekly for three fractions.5 The
total dose was increased to 32 Gy based on
clinical experience of the radiation oncologist in
treating canine and feline patients with oral
melanoma, and with the goal of achieving a better
local response with 32 versus 24 Gy. Regional
lymph nodes were not irradiated because of
normal appearance on the original CT scan.
Radiation therapy was administered using a
Varian Clinac IX linear accelerator (Varian Medical Systems, Palo Alto, California 94304, USA).
A treatment depth of 5.0 cm was selected based
on the size of the tumor and in order to spare the
underlying maxillary gingiva. Manual planning of
an electron field using 16 MeV electrons at 100cm skin-to-surface distance was formulated. The
gross tumor volume was determined to be the
measurable disease seen on the pretreatment CT
scan. A clinical target volume (CTV) of 1 cm was
established to include any potential microscopic
disease. A patient target volume (PTV) of 1 cm
around the CTV was established, and the treatment was planned to include the PTV within the
90% isodose line.
A custom Cerrobend electron mold was made
on the first treatment day in order to contour the
15-cm electron cone opening to adequately treat
the tumor and spare the surrounding normal
tissues. The lion was positioned in right lateral
recumbency with its head toward the gantry. An
angled Styrofoam wedge was used to level the
patient’s muzzle. The gantry of the linear accelerator was set to 08, and the central axis was
positioned in the center of the visible tumor.
Bolus material was placed around the tumor area
to establish a flat treatment surface, and to protect
the underlying normal tissues on the periphery of
the tumor area.
After two radiation treatments, the treatment
depth was changed to 4 cm because the tumor had
724
JOURNAL OF ZOO AND WILDLIFE MEDICINE
Table 1. Surface area of a dermal malignant melanoma in an African lion (P. leo) during external-beam
hypofractionated radiation and immunotherapies.
Date
11
21
28
06
12
26
01
a
b
Jun 2012a,b
Jun 2012a
Jun 2012a,b
Jul 2012a
Jul 2012b
Jul 2012b
Aug 2012
Length
(cm)
Width
(cm)
Thickness
(cm)
Surface
area
(cm3)
10
7.25
6.5
6.0
5.5
5.5
6.0
10
6.5
7.0
6.5
5.5
5.5
5.8
4.5
4.5
3.0
2.5
2.8
2.9
2.8
450
212
136.5
97.5
84.7
87.7
97.4
Radiation therapy performed.
Melanoma vaccine administered.
responded to treatment and was reduced in size.
The subsequent radiation plan was identical to
the first two treatments, with the exception of an
additional 1-cm bolus over the top of the tumor,
to once again limit the dose to the underlying
maxillary gingiva. Even though the tumor mass
had decreased both in length and width, the
treatment area was not changed in order to treat
any microscopic residual disease.
Throughout radiation and immunotherapy, the
melanoma continued to decrease in size (Table 1).
Complete blood counts and plasma biochemistries were performed at each treatment interval,
and no significant clinical abnormalities were
identified. A venous blood sample was also
collected for determination of anti-human tyrosinase titers at each immobilization. Acute radiation side effects detected were grade I alopecia
and pigmentation at the radiation site.
Approximately 2 mo after the diagnosis of
melanoma was made and following completion
of external-beam radiation, it was elected to
surgically excise the mass because of the reduction in size by approximately 50%. The lion was
anesthetized with the protocol described previously, and prior to surgical excision, a CT scan
was performed to reevaluate tumor margins and
possible invasion of regional lymph nodes. At the
time of immobilization, it was noted that the lion
had developed left submandibular lymphadenomegaly. A CT scan showed a decrease in size of
the melanoma and mild ipsilateral mandibular
lymphadenopathy that was most consistent with
metastatic disease.
It was elected to surgically excise the melanoma
along with the left submandibular lymph node.
The left side of the head and neck was clipped and
prepped from the nose to the fifth cervical
vertebra. In order to provide intraoperative local
anesthesia, an infraorbital nerve block was performed within the left maxillary infraorbital
foramen with 2 ml bupivacaine HCl (Hospira).
An incision was made over the enlarged submandibular lymph node, and blunt dissection was
performed to isolate the lymph node. The lymph
node and surrounding tissue were dark, and
enlarged consistent with metastatic disease. An
elliptical incision was made around the primary
mass, and the mass was dissected from the
surrounding subcutaneous and muscular tissues.
Streams of neoplastic tissue could be observed
following the paths of various blood vessels and
nerves of the left maxilla. Macroscopic excision
was deemed the best procedure for this lion. The
mass was removed en bloc, and both the primary
mass and the submandibular lymph node were
submitted for histopathology. Histopathology
found perinodal metastasis but no intranodal
metastasis present in the lymph node and incomplete excision of the primary melanoma.
The lion recovered from anesthesia and surgery
without complications and was administered
meloxicam (Metacam, Boehringer Ingelheim, St.
Joseph, Missouri 64506, USA; 0.2 mg/kg s.c.) and
tramadol (Pfizer; 2 mg/kg p.o. b.i.d. for 3 days) for
postoperative analgesia. Following surgery, the
animal was eating and acting normally and
showed no signs of disease or postoperative
complications.
Six months after surgical excision of the melanoma, the lion was immobilized for recheck
thoracic radiographs and melanoma vaccine administration. At that time, no physical evidence of
regional or distant metastatic disease was present,
and a small 3-cm round surgical dehiscence was
present at the primary surgical site. The dehiscence site was clean, and no additional masses
could be palpated in the area of the original
melanoma. A small raised area on the gum line of
the first left maxillary premolar was aspirated,
and cytology revealed low-grade inflammation
with no signs of metastatic disease. Thoracic
radiographs showed previously noted age-related
lung changes but no evidence of metastatic
disease. Hematologic and plasma biochemical
values were within normal limits. At the time of
writing, the lion is doing well and there is no
evidence of disease recurrence. The plan is to
continue vaccine administration and thoracic
radiographs every 6 mo for the rest of its life.
DISCUSSION
Melanomas are uncommonly diagnosed in
domestic cats12,13,15 and have been reported to
STEEIL ET AL.—MELANOMA IN A LION
affect the oral cavity, as well as ocular and
cutaneous tissue.12,13,15 Feline melanomas have a
variable degree of malignancy, with oral and
ocular forms being the most aggressive.15 At
present, malignancy is most accurately determined by histopathologic evaluation of the tumor.
Surgery is the treatment of choice for resectable
tumors and wide surgical margins, and adjunctive
treatment is suggested if margins cannot be
achieved.20 Adjunctive treatment consists of radiation therapy, chemotherapy, and/or immunotherapy. Survival rate in domestic cats with
melanoma has been reported to be dependent on
both malignancy and tissue site.15 This report
showed that the mean survival time of cats after a
diagnosis of malignant melanoma varied: oral, 61
days; ocular, 156 days, with four cats living past
255 days; and palpebral melanoma, 409 days.15
This case report describes surgical excision,
external-beam hypofractionated radiation, and
immunotherapy for the treatment of a dermal
melanoma in an African lion. Because of the size
and location of the tumor, surgical resection could
not be pursued as an initial step because of the
concern for the inability to close the wound
created after the mass removal. As a result,
external-beam hypofractionated radiation therapy
in conjunction with immunotherapy was performed with the goal to reduce tumor size for
surgical excision. In nondomestic felids, there are
few reports of patients with melanomas, and
information regarding treatment is scant.
Radiation therapy is considered an effective
modality for the treatment of patients with nonresectable or incompletely excised melanoma
tumors.6,16 Radiation planning for the lion reported here consisted of a CT scan, including administration of contrast. A standard external-beam
hypofractionated radiation plan for the treatment
of malignant melanomas in cats was used for the
lion in this report.5 One study demonstrated no
difference in the median survival rate in dogs with
oral melanoma treated with weekly-dose radiation versus daily radiation.16 Acute radiation side
effects are commonly seen in rapidly dividing
tissues such as skin, oropharyngeal mucosa,
intestinal mucosa, urinary bladder, and vaginal
mucosa. Common side effects observed in the
skin are erythema, dry or moist desquamation,
and dermal destruction.8,10 In the lion reported
here, acute side effects occurred at the site of
radiation therapy and included grade I alopecia
and pigmentation of the tissue surrounding the
tumor. Eleven months after the conclusion of
radiation therapy, no signs of late side effects have
725
been detected. Radiation therapy in domestic cats
is not commonly used for the treatment of
malignant melanomas, probably because of the
low incidence of this type of tumor in cats. One
study showed that 60% of cats had a partial or
complete response when treated with hypofractionated radiation therapy for oral melanomas.5
The median survival time of all cats in that study
was 146 days.5 Currently, the lion in this report
has survived for 390 days from the time of
diagnosis, and there is no evidence of disease
recurrence for 336 days from surgical excision.
Because of the aggressive nature of melanomas
and the known minimal and short-lived response
to conventional chemotherapy, additional adjunctive treatments were applied for this case. Immunotherapy is a novel treatment currently marketed
for the management of canine melanomas.1 Two
different types of melanoma vaccines have been
developed , but only one is commercially available.2,14 For canine malignant melanomas, the
human tyrosinase enzyme has been used in the
development of a xenogeneic vaccine because of
the high amount of tyrosinase present within
melanoma cells.3,11 A xenogeneic human tyrosinase vaccine has been developed that results in
inducing antibody and cytotoxic T-cell antitumor
responses in canine patients with melanoma that
receive it.3,11 The vaccine is most efficacious and
labeled for patients who have complete local
disease control. Occasionally, patients with gross
disease do have a response to the vaccine, but this
is not the norm.3 The homology of African lion
tyrosinase versus human tyrosinase is unknown;
however, it can be surmised that it is close to that
of the domestic cat, which is similar to that of the
domestic dog.18 Antibody responses to the human
tyrosinase melanoma vaccine have been shown to
coincide with long-term survival in dogs.11 The
rationale for the use of a human tyrosinase
vaccine in this lion was to slow or prevent future
metastatic disease. Currently at the authors’
institution, studies are being performed evaluating the human tyrosinase antibody response of
nondomestic felids with melanoma to the melanoma vaccine. No adverse vaccine reactions such
as pain, redness, or swelling at the injection site
were observed in the lion in this report. Treatment
with human tyrosinase vaccine improved longterm survival in dogs that had their primary tumor
excised even in the presence of advanced metastatic disease.3 It is unknown what the long-term
outcome will be for the lion in this report, but
currently there is no physical evidence of disease
in the lion.
726
JOURNAL OF ZOO AND WILDLIFE MEDICINE
In conclusion, dermal melanomas in exotic
felids are infrequently reported. Diagnostic and
treatment modalities for this type of tumor
include biopsy, fine-needle aspiration of regional
lymph nodes for cytology, complete blood count,
chemistry panel, thoracic radiographs, surgical
excision, external-beam hypofractionated radiation, chemotherapy, and immunotherapy. In the
case presented here, external-beam radiation and/
or immunotherapy was effective in reducing
tumor size to facilitate surgical excision. Currently, immunotherapy with a melanoma vaccine is
approved only for domestic dogs, and its use in
nondomestic animals is considered off label. The
effectiveness of immunotherapy in developing an
immune response in this lion is under investigation. Further studies need to be performed to
determine if there are any side effects to either
external-beam hypofractionated radiation or immunotherapy with a melanoma vaccine in exotic
felids.
Acknowledgments: The authors thank the staff
at Tiger Haven Inc., especially Debbie Wilkins
and Mary Lynn Haven, for the care and treatment
of this lion.
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Received for publication 12 February 2013