Nondomestic, Exotic, Wildlife and Zoo AnimalsReview

Neoplasms of the Urinary Tract in Fish

Veterinary Pathology
2014, Vol. 51(5) 1000-1012
The Author(s) 2013
Reprints and permission:
sagepub.com/journalsPermissions.nav
DOI: 10.1177/0300985813511122
vet.sagepub.com

E. D. Lombardini1, G. C. Hard2, and J. C. Harshbarger3

Abstract
The veterinary literature contains scattered reports of primary tumors of the urinary tract of fish, dating back to 1906. Many of the
more recent reports have been described in association with the Registry of Tumors in Lower Animals, and most of the spontaneous
neoplasms of the kidney and urinary bladder are single case reports. In rare instances, such as described in nephroblastomas of
Japanese eels and tubular adenomas/adenocarcinomas of Oscars, there is suggestion of a genetic predisposition of certain populations to specific renal neoplasms, environmental carcinogenesis, or potentially an unknown infectious etiology acting as a promoter.
Hematopoeitic neoplasms have been infrequently described as primary to the kidney of a variety of fish species, and therefore those
case reports of renal lymphoma and plasmacytic leukemia are addressed within the context of this review.
Keywords
fish and marine animals, wildlife, urinary tract, oncology
Between 30 000 and 40 000 species of fish have been reported
in the literature and included in a variety of taxonomic classes
falling under the infraphylum Gnathostomata or jawed vertebrates, which further consists of the extant class Chondrichthyes or cartilaginous fish and superclass Osteichthyes
or the bony fish.37 Within that enormous number of species,
there is an extraordinary variety of structure and physiology,
with species ranging in size from the smallest recorded fish
(Paedocypris progenetica), measuring a mere 7.9 mm,48 to the
whale shark (Rhincodon typus), measuring up to 20 m in
length.15 It is therefore reasonable to expect that the pathology
of fish encompasses an immense domain of entities and pathogeneses, representing a boundless field of potential discovery
in veterinary pathology, particularly concerning spontaneous
neoplastic disorders. The current paucity of information is due
in large part to the environment in which the subjects live, the
lack of our ability to track individuals throughout their range,
and the fact that autolysis and predation affect the vast majority
of samples, leaving the pathologist with a limited caseload of
spontaneous neoplasms within wild populations. On the other
hand, zoo and aquarium populations, private tropical and
marine aquaria, and farmed fish are providing veterinary
pathologists with a steady flow of novel entities and new interactions between host species and disease.
The following review of neoplastic disease in the urinary
system of bony and cartilaginous fishes relies heavily on the
body of knowledge accumulated by the National Cancer
Institutes Registry of Tumors in Lower Animals (RTLA)
(Experimental Pathology Laboratories, Inc, Sterling, VA),
which were donated from myriad sources as well as from the
diligence of those researchers who have published their findings in the international literature. In addition, other sources
were consulted as part of this review to include the Armed

Forces Institute of Pathology (AFIP) archives, the Smithsonian

National Zoo, department of pathology, and through the generous inclusion of selected syngnathid tumors from the Toronto
Zoo.
The histopathology of most of these exemplars from the
RTLA and the AFIP were reexamined, and photomicrographs
from selected cases are included in this article. The RTLA
alone consists of a collection of more than 7500 pathologic
specimens of cold-blooded vertebrates and invertebrates with
historical data and pertinent literature.19 In addition, this
review carefully examined both current and historical literature
dating back more than 100 years and scoured all references to
neoplastic lesions within the urinary tract of fish.
The veterinary literature contains scattered reports of
primary tumors of the urinary tract of fish dating back to
1906. Many of the more recent reports have been described
in association with the RTLA, and the vast majority of the
spontaneous neoplasms of the kidney and urinary bladder are
single case reports. In rare instances, such as described in
nephroblastomas of Japanese eels (Anguilla japonica) and
tubular adenomas/adenocarcinomas of Oscars (Astronotus
ocellatus), there is suggestion of a genetic predisposition of
certain populations to specific renal neoplasms, environmental

Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand

Private Consultant, Tairua, New Zealand
3
Department of Pathology, George Washington University Medical Center,
Washington, DC, USA
2

Corresponding Author:
E. D. Lombardini, Armed Forces Research Institute of Medical Sciences,
USAMC-AFRIMS, APO AP, 96546.
Email: [email protected]

Downloaded from vet.sagepub.com at American College of Veterinary Pathologists on August 31, 2015

Lombardini et al

1001

carcinogenesis, or potentially an unknown infectious etiology

acting as a promoter. Hematopoeitic neoplasms have been
infrequently described as primary to the kidney of a variety
of fish species, and therefore those case reports of renal lymphoma and plasmacytic leukemia will be addressed within the
context of this review.
Primary renal neoplasia in higher vertebrates is predominantly split into the 2 most common forms, being nephroblastomas and some variant of adenocarcinomas. This appears to be
statistically true within fish as well, with the vast majority of
both spontaneous and experimental renal neoplasms falling into
one or the other diagnostic group. The important distinction lies
in the prevalence of primary renal lymphoma in fish due to the
particularities of renal anatomy and physiology in those affected
species. The most common renal tumor in domestic species is
lymphoma, but these are almost all metastatic processes with the
potential exception of chickens affected with Gallid herpesvirus
type 2 or avian leucosis virus.60
Few classical spontaneous renal neoplasms have been
unequivocally diagnosed in fish. Of these, nephroblastomas far
exceed other tumors in prevalence, with 83 cases having been
either catalogued within the RTLA archives or described within
the literature. Japanese eels and, to a lesser extent, rainbow trout
(Oncorhynchus mykiss) represent greater than 50% of all individual cases, but 16 distinct species of fish have been reported
with nephroblastomas. The second largest group of spontaneous
renal neoplasms consists of the epithelial tumors comprising various subtypes of benign adenomas and approximately equal
numbers of adenocarcinomas. All told, these have been
described in 17 diverse species and are typically believed to arise
from terminally differentiated tubular epithelium.
A variety of chemical etiological causes have been attributed
to piscine carcinogenesis in the veterinary literature, including
methylazoxymethanol acetate (MAM), N-methyl-N0 -nitro- Nnitrosoguanidine (MNNG), dihydroepiandrosterone (DHEA),
multiple aflatoxins, nitrosamines, and polynuclear aromatic
hydrocarbon (PAH), and while these compounds have been primarily reported to induce hepatic tumors, there are several
reports of nephroblastomas in association with a confirmed
carcinogen.13 Other environmental studies examining epizootics
of hepatocellular and biliary carcinomas in Brown bullhead
catfish (Ameiurus nebulosus),6,7,70 lake whitefish (Coregonus
clupeaformis),61 and English sole (Pleuronectes vetulus)54,57 and
exocrine pancreatic tumors in mummichog (Fundulus heteroclitus)18 have also shown a direct correlation between water
contaminants and neoplastic transformation in various target
tissues.
Retroviruses have been associated with tumor formation in
an ever expanding cohort of species, as have reports of DNA
viruses such as herpesvirus, papovavirus, and adenovirus.1,12,45,46 One of the most comprehensively researched
species-specific epizootics of piscine tumors are the damselfish
neurofibromatosis and chromatophoromatosis, which have
been associated with retroviruses.13,76 Examples of similar outbreaks associated with retroviral etiologies include lymphomas
in muskellunge (Esox masquinongy),81 northern pike (Esox

lucius),85 and madai (Pagrus major),63 as well as epidermal

tumors in white sucker (Catostomus commersoni),82 walleye
(Sander vitreus),87 and smelt (Osmerus mordax).1 While none
of these are associated with renal-specific targeting for carcinogenesis, there have been several reports of primary renal and
metastatic lymphomas associated with retroviral neoplastic
transformation. Salmonid herpesvirus type 2, colloquially
known under a variety of names, such as Yamame tumor virus,
Coho salmon herpesvirus, rainbow trout kidney virus, and
Nerka tumor virus, among others, has been reported to form
renal epithelial tumors in masu salmon (Oncorhynchus masou),
sockeye salmon (Oncorhynchus nerka), chum salmon (Oncorhynchus keta), Coho salmon (Oncorhynchus kisutch), and
rainbow trout, but the primary tumors are typically found
within cutaneous tissues.45 The virus causes age- and isolatecorrelated high rates of mortality, with experimentally infected
rainbow trout having rates ranging from 34% to 77% mortality.
In surviving salmonids, tumors may develop in up to 100% of
infected fish within a population.20 Additional tumorassociated herpesviruses that result in systemic disease include
Herpesvirus cyprini, herpesvirus of Japanese flounder, and epizootic epitheliotropic disease virus of lake trout (Salvelinus
namaycush).2
Familial or breed-specific renal tumors have been reported
in humans, German Shepherd dogs, and Eker rats, associated
in humans with molecular change within the von-Hippel Lindau (VHL) tumor suppressor gene, while the Eker rat is an animal model for hereditary renal carcinogenesis due to the
development of renal carcinomas associated with mutation of
the Tsc-2 tumor suppressor gene. In German Shepherd dogs,
tumor induction is associated with a missense mutation in the
Birt-Hogg-Dube (BHD) gene, which is a tumor suppressor
gene located on chromosome 5. Although the genetic interplay
between several of the retroviral-induced tumors and their
hosts genome has been closely examined,73 to date the spontaneous renal tumors described in fish have not been shown
to have a familial predisposition with the exception of Japanese
eels and the development of nephroblastomas, which appear to
show multiple nucleic acid changes associated with the Wilms
tumor 1 gene.64

Renal Neoplasms
Nephroblastomas
Nephroblasma is traditionally described as a tumor composed
of neoplastic cells originating from the embryonic kidney,
specifically in higher vertebrates such as humans, from the
metanephric blastema. In these cases, the tumors develop from
shared stem cells during embryogenesis or from embryonic
nephrogenic rests and undergo transformation into neoplastic
blastema and stromal cells. The tumor is a relatively common
disease in humans, in whom it is termed Wilms tumor, but has
been described also in most domesticated veterinary species,29
laboratory animals,30 and some exotic species.30,80 In pigs and
chickens, it is considered the most common primary renal

Downloaded from vet.sagepub.com at American College of Veterinary Pathologists on August 31, 2015

1002

Veterinary Pathology 51(5)

tumor and the second most common in cats and dogs.60 In

humans, familial forms of the disease exist in which the Wilms
tumor gene, located on chromosome 11, is correlated to tumorigenesis. WT-1 is implicated in approximately 22% of human
cases, while WTX and CTNNB1 genes, both involved in the
WNT/beta-catenin signaling pathway, account for an
additional 20% to 30% of human nephroblastomas with minimal overlap between the genes involvement.55,75 Furthermore,
rat models have been developed using strains of SpragueDawley and Noble Hooded rats, which have demonstrated
nephroblastoma development as a spontaneous process31,59 as
well as through experimental induction using chemical
carcinogenesis.32,79
With the exception of lymphoma, nephroblastomas represent the most common primary renal neoplasm in fish, having
been reported in both spontaneous and carcinogen-induced
instances and affecting a wide variety of fish species.
Epizootics of spontaneous nephroblastoma have been reported
in over 60 Japanese eels,56,64 while individual cases have been
reported in European eels (Anguilla argentina),21 striped bass
(Morone saxatilis),38 koi (Cyprinus carpio),84 Crucian carp
(Carassius carassius),10 Japanese dace (Tribolodon hakonensis),58 smelt,42 Siamese fighting fish (Betta splendens),52 sockeye salmon (RTLA), rose bitterling (Rhodeus ocellatus),34
banded cichlid (Heros severus),24 and rainbow trout.22,25,66,74
While a definitive correlation to a specific etiology resulting
in the high incidence of nephroblastomas in the Japanese eel
has not been proven, the authors of the various articles suggest
that a water vector or carcinogen cannot be ruled out, and 1
unpublished report suggested the presence of virions in correlation with an eel affected with a concurrent nephroblastoma.62
The carcinogen theory is consistent with extensive research
conducted in rainbow trout, which have been demonstrated to
undergo neoplastic transformation to nephroblastoma when
experimentally exposed to both dimethyl nitrosamine (DMN)
and N-methyl-N0 -nitro-N-nitroguanidine (MNNG).5 Furthermore, studies examining the environmental impact of MAM
have produced neoplastic transformation in several visceral
organs in a variety of species, including guppies (Poecilia reticulata), zebrafish (Danio rerio), and medaka (Oryzias latipes).
The predominant populations of neoplasms were concentrated
within the liver of each individual species, but medaka produced rare nephroblastomas when exposed to the carcinogen.23
While the clinical presentation in reported cases varies,
several examples in the literature displayed some form of vertebral pathology, such as lordosis, combined with coelomic
enlargement. The gross presentation also typically includes
organ displacement and the presence of a large, firm, pale,
frequently unencapsulated mass. Nephroblastomas vary in size
from small protuberances within the kidney tissue of less than
half a centimeter in diameter to large growths, attached to the
dorsal body wall, displacing the abdominal viscera. The biggest
nephroblastoma in the RTLA collection occurred in a 32-cmlong rainbow trout and measured 7  8.5 cm. Most descriptions
indicate the surface of trout nephroblastoma to be smooth,
sometimes lobulated, and grayish to darkly pigmented. On cut

section, the neoplasms are frequently white to pale beige and

either firm and often granular or cystic in texture. Tissue of origin also varies between species, with all incidents in Japanese
eels arising exclusively from the posterior aspect of the kidney.
The same is reported in the case of koi, while the spontaneous
reports in Siamese fighting fish, rainbow trout, striped bass,
and Japanese dace appear to have obliterated the majority of
both the anterior and posterior kidneys by the time of presentation, thereby negating the ability to definitively determine an
anatomical point of origin (Fig. 1). Considering the variety in
anatomic structure of fish kidneys, the embryological development of the anterior pronephros and the posterior opisthonephros, and the differences in glomerular vs aglomerular fish,
it is unlikely that nephroblastomas are strictly limited to the
genesis within the posterior kidney in all fish, but it stands to
reason that those species with an anterior kidney predominantly
composed of hematopoetic and endocrine tissues are overwhelmingly reported to have nephroblastomas developing in the
posterior kidney. Predominantly, nephroblastomas in fish
appear to be locally aggressive, expansile, and frequently cystic
but rarely metastasize to distant sites. However, the reports in
Crucian carp, Japanese dace, rainbow trout, and Japanese eels
have described metastases to distant organs within affected
animals.50
Microscopically, fish nephroblastomas appear to be consistent with the traditional triphasic histopathological appearance
of the tumors in humans. The 3 diagnostic criteria include some
combination of blastemal, epithelial, and mesenchymal elements, with the presence of embryonic or abortive glomerular
structures considered as the most critical.60 Those exemplars of
piscine nephroblastomas described in the literature to date
include tumors that predominantly present as large masses that
efface the preexisting renal parenchyma. The majority are
described as being unencapsulated and poorly demarcated,
with infiltration into the renal interstitium, separating, surrounding, and replacing the renal tubules and glomeruli (Suppl.
Fig. S5). The neoplasms are composed of the 3 distinct cellular
populations in varying degrees of development and in various
ratios. These include the epithelial component frequently
arranged in disorganized tubules lined by cuboidal to columnar
cells and tufts of epithelium with the appearance of embryonic
or primitive glomeruli that invaginate into a luminal space
lined by flattened cells similar to the parietal epithelium of
Bowmans capsule (Fig. 2). The blastemal population is characterized by small polygonal cells with minimal cytoplasm and
dense nuclei with indistinct nucleoli, arranged in large swaths
or smaller nodules (Suppl. Fig. S6 and Fig. 3). The final element is the primitive mesenchyme, composed of loose streams
and whorls of spindle to stellate cells with scant cytoplasm and
elongate nuclei. Within the mesenchymal population, there are
frequent reports of terminal differentiation of the cells into
striated muscle, cartilage, or even bone and, as such, form
irregular islands of these tissue types. The mitotic rate in each
population is extremely variable between reports.
The RTLA archive contained single cases of nephroblastoma in 4 other species of the salmonid family besides the

Downloaded from vet.sagepub.com at American College of Veterinary Pathologists on August 31, 2015

Lombardini et al

1003

Figure 1. Kidney; Chinook salmon (Oncorhynchus tshawytscha). Markedly replacing and effacing the kidney and obscuring the coelomic cavity is a
densely cellular neoplasm (asterisk). Hematoxylin and eosin (HE). Figure 2. Kidney; Chinook salmon (O. tshawytscha). Piscine nephroblastomas
are composed of the same 3 neoplastic cell populations described in higher vertebrates. This photomicrograph demonstrates the epithelial cells
forming disorganized tubules and rare primitive glomeruli surrounded by swaths of blastema characterized by dense swaths of small polygonal
cells. HE. Figure 3. Nephroblastoma; Siamese fighting fish (Betta splendens). In addition to the epithelial and blastemal component, fish nephroblastomas are also composed of populations of primitive mesenchyme, which frequently surrounds the disorganized tubules. HE. Figure 4.
Nephroblastoma; Siamese fighting fish (B. splendens). Occasionally, within certain species, fish nephroblastomas have been described with
prominent coalescing islands of cartilage. HE. Figure 5. Kidney; Oscar (Astronotus ocellatus). Replacing the renal parenchyma is a renal adenoma
composed of epithelial cells forming papillary projections into cystic regions. HE. Figure 6. Coelom cross section; yellow seahorse (Hippocampus kuda). Obscuring and effacing the coelomic cavity and replacing the viscera is a multinodular, expansile neoplasm diagnosed as a renal adenoma. HE. Figure 7. Kidney; polka dot sting ray (Potamotrygon leopoldi). Replacing and mildly compressing the renal parenchyma is a highly
vascular renal adenoma (arrows). HE. Figure 8. Kidney; Polka dot sting ray (P. leopoldi). Replacing the renal parenchyma is a neoplasm composed
of densely packed polygonal cells with abundant eosinophilic, finely granular cytoplasm. At high magnification, there is approximately 1 mitotic
figure per field (arrow). Occasionally, the neoplastic cells recapitulate vague tubules. HE. Figure 9. Kidney; banded cichlid (Heros severus).
Replacing the kidney is a neoplasm composed of polygonal cells arranged in distinct tubules. This particular tumor was diagnosed as an adenocarcinoma due to regions of desmoplasia and regional anaplasia of neoplastic cells. HE.

rainbow troutnamely, brown trout (Salmo trutta), Coho salmon, Chinook salmon (Oncorhynchus tshawytscha), and chum
salmon. In the former 3 species, the tumors histologically fell
within the range expressed by the rainbow trout nephroblastomas, with primitive glomerulus formation in the brown trout
specimen, loose sheets of blastema with minimal epithelial
differentiation in the Chinook salmon, and squamoid differentiation within blastemal islands in the Coho salmon. The latter
tumor had invaded skeletal muscle of the dorsal body wall.

Two nephroblastomas encountered in striped bass, one in a

Siamese fighting fish and one in a brown bullhead, exhibited a
feature not described in the salmonid renal neoplasms. In addition to the pathognomonic presence of blast cell aggregates and
differentiation into primitive tubules, cartilage was a prominent
feature of the bass and the Betta neoplasms. The cartilage was
distributed histologically as either disorganized solid sheets or
small islands of mature chondrocytes often separated and surrounded by contiguous areas of blastema and tubules (Fig. 4).

Downloaded from vet.sagepub.com at American College of Veterinary Pathologists on August 31, 2015

1004

Veterinary Pathology 51(5)

Derivation of the cartilage by direct differentiation from

blastema appeared probable but is not proven.
A series of tumors diagnosed as nephroblastoma in eels
presented an important departure from those seen in the rainbow trout. Thirty-nine tumors are held in the RTLA files, 38
of them from Japanese eels and one from an American eel
(Anguilla rostrata). A single case has also been recorded in the
silver eel (Anguilla anguilla).21 Collectively, these tumors displayed a histological spectrum more reminiscent of human
Wilms tumors.
As a group, the Japanese eel tumors presented a histologic
pattern that was, for the most part, similar to that of salmonid
nephroblastomas, including diffuse sheets of basophilic blast
cells with some fascicular disposition, irregular tubular structures, squamoid differentiation, and primitive glomerulus
formation. However, most of the eel tumors, including that in the
American eel, were also admixed with atypical striated muscle
ranging from misshapen or round cells to bundles of more typical elongated myotubes. The silver eel tumor is described as having areas of cartilage and osteoid but no striated muscle fibers.
Consistent with published descriptions and illustrations,49,56
some of the nephroblastomas in Japanese eels displayed a striking admixture of poorly to well-formed striated muscle cells
with diffuse blastema and tubular and glomeruloid structures.
The islands of muscle cells were sometimes in intimate
juxtaposition with the undifferentiated blast cells, suggesting
transitional stages between the blasts and the rhabdomyoblasts.
In this series of neoplasms in eels, it became unambiguously
evident that striated muscle can be one product of differentiation of neoplastic renal blastema, as is sometimes the case in
human nephroblastomas.
Viewed as a series, these tumors in eels represent a spectrum
ranging from purely epithelial nephroblastoma to embryonal
renal tumors with increasing degrees of differentiation into
striated muscle, with all examples retaining to some extent a
diffuse distribution of blast-like cells and some distinct tubule
formation. Human Wilms tumor, which predominantly affects
children, also comprises a spectrum of histological variants
ranging from purely blastemal and epithelial forms (the majority of human nephroblastomas) to neoplasms consisting of
blastema, differentiated into tubule profiles, and neoplastic secondary mesenchyme in the form of sarcoma cells and striated
muscle. It is this potential for biphasic differentiation into neoplastic elements of secondary mesenchyme as well as into
epithelium that is connoted by the term Wilms tumor in
humans. Anguilla spp is the only fish genus in which renal
neoplasms resemble human Wilms tumor with respect to a
capacity for rhabdoid differentiation.
As discussed earlier, nephroblastomas have been experimentally induced through administration of 2 different nitroso
compounds. In the first of these experiments, rainbow trout
were fed doses of dimethylnitrosamine ranging from 7 to
1920 mg/100-g dry diet in their daily ration for 12 to 20
months.3 These various exposures to dimethylnitrosamine
resulted in a 1% incidence of nephroblastoma in the survivors.
Another study found that juvenile rainbow trout injected with

either single or repeated intraperitoneal doses of 100 mCi of

Iodine 131 had an increased incidence of nephroblastoma
formation.3,4
MNNG-induced nephroblastomas have been experimentally
associated through treating both embryonic and near-adult
stages of rainbow trout. In 1 study, MNNG was administered
by stomach tube to 12- to 15-month-old fish, and nephroblastomas of macroscopic size were observed within 12 months.44 In
another study, rainbow trout embryos were incubated in water
containing 10 ppm MNNG for 24 hours at 10 C. In this
instance, a nephroblastoma measuring approximately 4.5 cm
was observed at 9 months following carcinogen exposure. The
cumulative frequency of nephroblastoma in an effective group
of 122 survivors was 7.5% with the peak of tumor incidence
occurring at 15 months postexposure.45 Further investigations
have induced nephroblastomas in embryos after a single hour
of MNNG exposure.39 The histopathology of these experimentally induced nephroblastomas in salmonids and their variations with respect to the predominance of certain histological
features are the same as in the spontaneously occurring neoplasms described in the literature in other fish species.

Epithelial Tumors in Fish

There are only rare reports of spontaneous renal tubular cell
tumors in the literature occurring in fish, and many of those that
do appear range from a century ago. Equally, the RTLA
archives contain scarce submissions of either adenomas or carcinomas in fish. The few descriptions that do arise are often
mentioned without a histopathological description and as such
are of limited use in drawing population or interspecies correlates. In 1911 and again in 1924, cystic adenocarcinomas were
described in silver eels.72,78 Other early reports include a
benign renal tumor in a catfish composed of neoplastic cells
forming acini and papilliferous projections into cystic spaces,
suggestive of a renal papillary cystadenoma77 and a similar
spontaneous tumor that was described in the mesonephric duct
epithelium of a Chinook salmon.50 Single case reports can also
be found in goldfish, catfish,77 Mozambique tilapia (Oreochromis mossambicus),24 and yellow or spotted seahorses (Hippocampus kuda).51 Furthermore, a review of the RTLA archives
revealed submission of a renal papillary cystadenoma in a
winter flounder (Pleuronectes americanus), as well as references to similar tumors in a Tiger barb (Barbus tetrazona) and
in a penguin tetra (Thayeria obliqua).47
Renal Cystadenoma/Renal Tubular Adenoma. Oscars appear to
have a predisposition for some variant of renal adenomas, which
have recently been determined to be of proximal tubular origin.
There has been some debate on the cell of origin of these neoplasms, with the first having been described in 1996 but without
proffering a definitive diagnosis at the time. In that case, the
mass, which was composed of mildly pleomorphic epithelial
cells forming papillary projections into cystic regions, significantly effaced the renal parenchyma (Fig. 5). While determined
to be locally expansile and potentially regionally aggressive,

Downloaded from vet.sagepub.com at American College of Veterinary Pathologists on August 31, 2015

Lombardini et al

1005

there was no evidence of malignancy, and the authors proffered a

more benign categorization of the mass, with a favored diagnosis
of an epithelial papilloma of mesonephric duct origin.67 Similar
tumors of the posterior kidney were observed in 3 other Oscars
submitted to the RTLA archives. In these instances, the masses
were also predominantly expansile and cystic, with minimal
pleomorphism, and a low mitotic index, but 1 of the 3 appeared
to be invading the adjacent preexisting renal tissue and all 3 had
some degree of necrosis, as well as granulomatous inflammation
and in 1 case an accumulation of birefringent crystals. More
recently, an additional 6 animals have been described in the literature with tumors described as renal cystadenomas. These are
similarly described as being expansile neoplasms, composed of
disorganized cystic tubular structures or endophytic papillary
projections with cuboidal to columnar epithelium supported by
a fine fibrovascular stroma (Suppl. Fig. S7). In all cases, the neoplastic cells are noted to have minimal pleomorphism and a low
mitotic index.40
Exclusive of those described in Oscars, there are individual
case reports of renal adenomas scattered in the literature, including examples in a tilapia (Sarotherodon spilurus).28 Chinook salmon,50,53 brown bullhead,77 rainbow trout,50 and northern pike65
with experimentally induced adenomas in zebrafish and medaka.
For the most part, these are described as renal cystadenomas or
papillary cystadenomas; however, the RTLA archives include
examples of diagnoses of papillomas in various levels of the
urinary tract. These will be described in the section covering
the urinary bladder.
A population of Crucian carp was affected by an epizootic
of renomegaly. Upon necropsy, several of the animals were
found to have renal adenomas as well as a high percentage of
polycystic kidneys. The authors of that particular study
suggested that while polycystic kidneys may be a precursor
to adenoma, in Crucian carp and goldfish, there is a correlation
between the myxozoan Sphaerospora dykovae (previously
Sphaerospora renicola) infection and both hematopoietic cell
and renal epithelial hyperplasia.41
Another group of interest was brought to light in a recent
study of syngnathid mortality at the Toronto Zoo, which
determined a 4.1% incidence of neoplasia, and of those,
approximately 50% were associated with the kidney. The study
evaluated the postmortem findings of 172 deaths in captive
spotted or yellow seahorses, potbellied seahorses (Hippocampus abdominalis), and weedy sea dragons (Phyllopteryx taeniolatus). A total of 7 neoplasms and 2 lesions described as
neoplastic-like were identified, to include a renal adenocarcinoma, a renal adenoma, and 2 renal round cell tumors
interpreted to be lymphoma. The tumor diagnosed as a renal
adenoma was associated with a 2-year-old male yellow seahorse that had an expansile mass occupying approximately half
of the coelomic cavity (Fig. 6). Histopathological examination
of the tissue noted a renal neoplasm composed of variably sized
tubules often supported by a dense fibrovascular stroma. The
authors described minimal atypia but acknowledged that there
was moderate autolysis of the tissue, which confounded a
more detailed description.51

Recent necropsy of a polka dot sting ray (Potamotrygon leopoldi) in Thailand revealed a firm, pale, well-circumscribed,
expansile renal mass measuring 4  3.5 cm. Microscopic
examination of the mass noted a densely cellular polygonal cell
neoplasm (Fig. 7). Occasionally, the neoplastic cells formed
vague tubules. The neoplastic cells had abundant eosinophilic,
finely granular cytoplasm and oval nuclei with stippled
chromatin (Fig. 8). There was approximately 1 mitotic figure
per high-powered field and mild anisokaryosis. This neoplasm
was diagnosed as a renal cell adenoma and represents the first
report of a renal tumor in an elasmobranch and only the second
in a condrichthyan.
Experimentally Induced Renal Adenomas. Renal cystadenomas
have been reported in rainbow trout subsequent to exposure
to MNNG. These tumors occurred with a 40% incidence rate
32 months after experimental intoxication and occasionally
occurred simultaneously with nephroblastomas.50
A renal tubular adenoma was also described in a zebrafish as
an extrahepatic tumor resulting from a MAM-ac exposure in a
carcinogenesis study. While the authors directly correlate the
tumor to the experimental intoxication, the tumor represents
a single incidence.86
Adenocarcinomas/Renal Cell Carcinoma. Adenocarcinomas arising
from well-differentiated (but not postmitotic) tubule cells have
occurred spontaneously in an elasmobranch as well as in several
teleost species. They were single tumors in each case. Like
nephroblastomas, adenocarcinomas also have been induced
experimentally by chemicals in small aquarium species.
The RTLA archives contain few examples of spontaneous
renal adenocarcinoma, including individual descriptions in the
spiny dogfish (Squalus acanthias), banded cichlid, Mozambique tilapia (Oreochromis mossambicus), winter flounder, and
Chinook salmon. Each of these 5 tumors consisted of a population of epithelial cells forming tubules, without the aggregates
of blastemal cells that characterize nephroblastoma.
The example in a spiny dogfish is the only renal neoplasm
that has been found to date in the order of Squaliformes. The
tumor was attached to the dorsal body wall in the location of
the kidney. It consisted of well-formed tubules, often irregular
in shape, lined by a single layer of cuboidal to columnar epithelium usually having eosinophilic cytoplasm. The cells were
polarized, with basally disposed vesicular nuclei, each containing a single prominent nucleolus. In some neoplastic tubules,
there was papillary proliferation of the lining cells. Tubules
were surrounded by a desmoplastic stromal reaction that was
scirrhous in parts of the tumor where epithelial structures were
limited to islands and cords. Some epithelial cells in scirrhous
areas were more anaplastic, having increased cytoplasmic
basophilia and larger nuclei. Necrosis of epithelial lobules or
of intraluminal cells was prominent. The tumor was partially
enclosed by a fibrous envelope, and invasion of normal parenchyma was evident. Mitotic figures were found particularly
at the invasive periphery of the tumor.

Downloaded from vet.sagepub.com at American College of Veterinary Pathologists on August 31, 2015

1006

Veterinary Pathology 51(5)

Figure 10. Kidney; Mosambique tilapia (Oreochromis mossambicus). The renal parenchyma is effaced by an expansile neoplasm composed of
polygonal cells arranged in disorganized tubules supported by a fine fibrovascular stroma. Hematoxylin and eosin (HE). Figure 11. Kidney; Chinook salmon (Oncorhynchus tshawytscha). Invading the interstitium, separating and replacing renal elements is an adenocarcinoma composed of
tubules and papillary projections lined by multiple layers of neoplastic polygonal cells. HE. Figure 12. Kidney; winter flounder (Pseudopleuronectes americanus). The adenocarcinoma was composed of variably sized cystic areas lined by piled polygonal cells that displayed moderate atypia.
HE. Figure 13. Heart; silver dollar (Metynnis hypsauchen). Throughout this section, the cardiomyocytes are separated, surrounded, and infiltrated by neoplastic lymphocytes. HE. Figure 14. Kidney; brown bullhead catfish (Ameiurus nebulosus). Multifocally, the neoplastic cells of the
transitional cell papilloma undergo maturation to a goblet cell phenotype characterized by a large apical vacuole. HE.

The tumor in the banded cichlid was similar in appearance

to that described in the adenocarcinoma of the spiny dogfish.
Well-formed basophilic tubules were supported by a loose,
hypocellular stroma (Fig. 9). At the periphery of the tumor,
there was no evidence of a fibrous pseudocapsular reaction.
Mitotic figures were infrequent and nucleoli faintly staining.
The variant described in the Mozambique tilapia is of an
unencapsulated, multiloculated neoplasm composed of
neoplastic polygonal cells arranged in multiple layers of cells
lining tubules and papillary invaginations into the larger cystic
areas. The cells are supported by a fibrovascular to myxoid
stroma (Suppl. Fig. S8 and Fig. 10). The neoplasm was
restricted to the kidney, and while the unencapsulated edge
of the mass abutted the skeletal muscle of the body wall, no
invasion was noted.24
The renal adenocarcinoma in the Chinook salmon presented
with a more microcystic and occasionally papillary pattern in
which the tubules formed convoluted and anastomosing spaces.
The lining epithelium was frequently of a pseudostratified or
multilayered columnar type, with densely crowded nuclei and
some mitotic activity (Fig. 11). The stroma consisted mostly
of narrow vascularized strands of connective tissue running
between the plicated, dilated tubule-like structures, but there

were also large stromal tracts containing hematopoietic tissue

and normal proximal tubules, representing entrapped preexisting renal tissue.
The winter flounder was noted on necropsy to have a large
retroperitoneal mass that interdigitated with the intervertebral
depressions and compressed the adjacent skeletal muscle while
not invading either the musculature or the spinal column
(Suppl. Fig. S9). The renal architecture was replaced by myriad
coalescing cysts ranging up to 1 cm in diameter. Histopathologically, these were lined by disorganized simple to lightly
stratified layers of neoplastic columnar epithelium that often
formed papillary projections into the cyst lumen (Fig. 12).
Within the literature is a recent report of a captive bred adult
male yellow seahorse that at necropsy was noted to have an
expansile renal mass contiguous with the posterior kidney and
occluding a large portion of the coelomic cavity. Microscopically, the mass was described as being a poorly encapsulated
neoplasm that effaced and replaced the preexisting renal parenchyma. Neoplastic cells were polygonal, separated by a fine
fibrovascular stroma and arranged in irregular cords, nests, and
rare acini or tubules. Neoplastic cells had indistinct cell
borders, a moderate amount of fibrillar or microvacuolated
eosinophilic cytoplasm, and large centralized nuclei with

Downloaded from vet.sagepub.com at American College of Veterinary Pathologists on August 31, 2015

Lombardini et al

1007

minimal anisocytosis and anisokaryosis (Suppl. Fig. S10). The

mitotic rate averaged approximately 2 per high-powered field,
and there was frequent single-cell necrosis with no significant
inflammation. A well-demarcated portion of the neoplasm consisted of a marked desmoplastic response admixed with high
numbers of melanomacrophages.51
Experimentally Induced Renal Adenocarcinomas. In carcinogenesis
studies, the guppy and medaka are reported to have developed
papillary renal adenocarcinomas secondary to experimental
exposure to polycyclic aromatic hydrocarbons.35 The chemical
was administered in the ambient water at varying concentrations for a brief period of exposure in posthatched fish. Three
guppies and 1 medaka that had been examined between 36 and
50 weeks posttreatment were submitted to the RTLA. They had
renal lesions ranging from hyperplasia of the proximal tubules
to frank renal adenocarcinoma. The latter was identical in form
to a tumor described in Chinook salmon, consisting of a convoluted pattern of anastomosing tubules lined by mitotically
active and densely crowded, basophilic columnar cells. Of
interest are renal neoplasms described as having occurred
within laboratory settings in zebrafish and demonstrated a notable difference in response to exposure to treatment with MNNG
in comparison with trout. Zebrafish exposed during development to MNNG have developed both renal adenomas and
adenocarcinomas but do not develop the typical nephroblastomas noted in trout fry with incidence rates upward of 50%.83

Lymphoma/Leukemia
Hematopoietic tumors of the kidneys of fish are described with
some frequency in comparison with other types of neoplasm,
and as opposed to mammals and birds, there is an anatomical
basis for a lymphoma to be primary to the kidney. Lymphomas
have been described in up to 22 species of fish, with the thymus
and kidney being statistically the most common primary sites
for neoplastic transformation.8,9,16,17,68 Historically, the species variation and histological anatomy of the fish kidney may
have resulted in inaccurate diagnoses of lymphoma in the
kidney. The normal presence of hematopoietic tissue within the
anterior kidney of many fish species may have resulted in exaggerated descriptions of both mononuclear cell nephritis and
lymphoma being maintained within the earlier published literature. In reviewing reports from a century ago, cases have been
evaluated based on both gross findings of a mass effect as well
as the histopathological appearance of the kidney. An example
of this is illustrated in the description of a lymphoma in the kidney of a conger eel (Conger oceanicus) published in 1931. In
this case, the neoplastic cells are characterized as lymphocytes
widely separating entrapped uriniferous tubules and compressing the preexisting renal tissue. Combined with a macroscopic
description of a 16  9  7 cm mass expanding the anterior
kidney, causing a bulging of ventral body wall, there is little
doubt of the mass effect and the presence of the described
tumor; however, the author himself cautions the reader of the

fact that the kidney of teleosts is an extremely lymphocytic

structure.88
Typically, the histopathological descriptions of lymphoma
in the fish kidney are similar to those in higher vertebrates.
Reports consist of highly invasive round cell neoplasms that
infiltrate, replace, and efface the renal architecture, forming
sheets of distinct lymphoblastic cells separated by preexisting
tissue. These cells often have a high nuclear to cytoplasmic
ratio and a moderately high mitotic index with mild anisocytosis and anisokaryosis. Frequently, these tumors are noted to
have metastasized widely throughout the viscera (Fig. 13).27,36
Lymphoreticular tumors in northern pike from Ireland and
in muskellunge from Canada have been shown to have a
retroviral etiology, and unlike other forms of spontaneous
lymphoma, both of these species-specific tumor types have a
seasonal incidence and have been described as beginning
within the cutaneous tissues and metastasizing to the viscera,
including the kidney. Histopathologically, both lymphomas
consist of uniform populations of round cells with a blastoid
appearance. The northern pike variant has a tendency to have
a starry-sky appearance, which is reported not to occur in the
muskellunge counterpart.33
An epizootic in pen-raised Chinook salmon resulted in significant mortality in multiple production sites in British Columbia in the late 1980s and 1990s. The disease was colloquially
known as marine anemia and was characterized by antemortem
gill pallor and bilateral exophthalmos. Necropsy of selected
animals revealed renal and splenic enlargement with the kidneys being uniformly enlarged and pale. Histopathologically,
the affected tissues were severely infiltrated by innumerable
neoplastic cells described by the authors as plasmablasts. The
renal interstitium was markedly expanded by the neoplasm,
and frequently there was evidence of a glomerulopathy consisting of expansion of the glomeruli by leukocytes with concurrent thickened basement membranes and hyperplasia of the
Bowmans capsule parietal cells. In one epizootic, the renal
lesions in 50% of the fish were complicated by the presence
of granulomatous inflammation with intracytoplasmic bacilli
suggestive of Renibacterium salmoninarum. The same
neoplastic cells were noted within the splenic vasculature, the
heart, the intestinal tract, hepatic sinusoids, and the choroid
gland. The neoplastic cells were characterized histopathologically and ultrastructurally as round cells with a large, clefted
nucleus and with distinct nucleoli. Electron microscopy noted
an abundant, regimented rough endoplasmic reticulum with
occasionally dilated cisternae suggestive of Russel bodies.
On the basis of these findings, the authors proffered a diagnosis
of plasmacytoid leukemia. Plasmacytomas have been described
in several fish species, and a single case of plasma cell leukemia has been described in a brown bullhead catfish. The reports
in Chinook salmon proved critical as the tumors were found to
be experimentally transmissible with cell-free filtrates, and
reverse transcriptase activity was noted, suggesting a retroviral
etiology.43
A variety of case reports have described lymphoma in the
kidneys of fish to include brook trout (Salvelinus fontinalis)16

Downloaded from vet.sagepub.com at American College of Veterinary Pathologists on August 31, 2015

1008

Veterinary Pathology 51(5)

and several animals culled during a mass mortality in lake trout

in New England. In those cases, the renal architecture was
effaced by a clonal proliferation of atypical lymphocytes characterized by sheets of round cells with moderate pleomorphism, hyperchromatic nuclei, and a markedly increased mitotic
index. These cases were interesting in that they were animals
having concurrent severe mixed bacterial infections and necrotizing cellulitis due to the combined presence of the neoplasm
and the bacteria. This particular study was not able to
definitively prove a viral etiology; however, based on the high
mortality in multiple locations, it is highly suggestive of an
oncogenic and potentially immunosuppressive virus resulting
in the transmission of disease and the high incidence of concurrent bacterial infections.17 Another interesting series involves
the previously described round cell neoplasms in 2 adult male
seahorses. In the first animal, 90% of the coelomic cavity was
filled with a large pale mass, composed microscopically of
sheets of round cells compressing preexisting parenchyma and
rare uriniferous tubules (Suppl. Fig. S11). The neoplastic cells
had indistinct cell borders, a high nuclear to cytoplasmic ratio,
large oval nuclei with roughly clumped chromatin, and a distinct central nucleolus. The cells displayed mild to moderate
anisocytosis and anisokaryosis and a high mitotic ratio. The
neoplastic cells were noted within the vasculature and had
metastasized to the intestinal wall. The second case was essentially identical, with increased pleomorphism and a greater
degree of tissue invasion and necrosis (Suppl. Fig. S12). While
immunohistochemistry was not pursued in these cases, the
morphology strongly favored a diagnosis of lymphoma.51

Urinary Bladder and Collecting Duct Tumors

As previously discussed, there appears to be a predilection in
Oscars for epithelial neoplasms of the urinary tract, with 10
cases having been described in the literature and some having
been observed but not published.26,40,69 Four neoplasms in the
RTLA archive were originally described as likely having
originated from the transitional epithelium lining the renal collecting ducts and urinary bladder. All 4 cases were discovered
in Oscars, although the individual specimens were separated by
both time and geographic location. Grossly, the 4 tumors were
huge nodular masses, up to approximately 8 cm in diameter, in
the caudoventral region of the abdomen with 1 protruding from
the anus. They appeared to originate in the transitional epithelium lining the collecting duct urinary tract system. However,
the exact point of origin, whether in the collecting ducts or the
bladder, was not determined. Histologically, the masses formed
cysts with neoplastic cells that were characterized as a cuboidal
to columnar epithelium forming papillary projections supported by a fine fibrovascular stroma (Suppl. Fig. S13). These
projections often invaginated into the lumina of the cystic
spaces. Some cysts contained acidophilic material resembling
proteinaceous casts. Also consistent with a renal origin, 2 of the
tumors contained birefringent urate crystals with the characteristic radiating pattern. As such, these tumors were interpreted
to be urothelial adenopapillomas of the urinary bladder/urinary

collecting duct system. A second study in Oscars collected

samples from 5 animals from various locales in Europe and
compared them microscopically and ultrastructurally with the
previously described US cases. Histopathologically, all
neoplasms were determined to be morphologically similar, characterized by partially encapsulated, densely cellular masses that
replaced a significant portion of the renal parenchyma. Neoplastic cells were polygonal, arranged in variably sized tubules,
which occasionally were markedly dilated and cystic. Multifocally, the neoplastic cells formed similar papillary projections
to those previously described. Neoplastic cells had indistinct cell
borders, a moderate amount of eosinophilic cytoplasm, basilar or
central nuclei with granular or finely stippled chromatin, 1 to 3
distinct nucleoli, and a low mitotic index (Suppl. Fig. S14).
Occasionally, the cells were covered in cilia. Only 1 of the 5
cases in this second study was thought to have progressed to the
point of malignancy and was noted to be invading the adjacent
renal tissue. Based on the concomitant presence of the cilia and
ultrastructurally of microvilli in these 5 cases, as well as those
RTLA cases examined in conjunction with this report, the
authors suggested that these tumors originated from the proximal
tubules rather than the urinary bladder, collecting duct, or the
mesonephric duct.40
In the literature, 2 mesonephric duct lesions have been
reported in rainbow trout that were exposed as fry to MNNG.50
These were cystic papillary growths of basophilic anaplastic
cells that projected into dilated luminal spaces. At the point
of attachment, they compressed the duct wall and periductular
connective tissue but did not breach the basal lamina. While
they were diagnosed as adenomas of the mesonephric duct, the
possibility of these lesions representing a hyperplastic or metaplastic response to an obstructive stimulus was also considered
based on their small size (approximately 1 mm) and their
proximity to a compressing renal cell cystadenoma in 1 case
and a nephrocalcinotic lesion in the other.
Several tumors involving the urinary bladder of fish have
been recorded in the literature over the past century as individual
case reports. The earliest description, which was published in
1909, appears to be that of a carcinoma involving the neck of the
urinary bladder in a goldfish.71,72 That particular tumor, which
obstructed the animals distended bladder, was reported as being
composed of epithelial cells in an alveolar arrangement. Another
instance was diagnosed as a squamous epithelioma associated
with crystal formation in the bladder wall of a cod (Gadus morhua).89 Furthermore, 3 similar tumors from specimens collected
in the Benares district of India were described as being large
rounded masses arising from the epithelial lining of the bladder
wall in a climbing gouramie (Ophiocephalus gachua), a spiny
eel (Mastacembelus armatus), and a ghost knife fish (Notopterus
notopterus). In all 3 cases, it was suggested that the lumen of the
urinary bladder was significantly compromised by the mass.
Unfortunately, there is little microscopic detail in the descriptions other than line drawings within the text.14
A more detailed description of a urinary bladder neoplasm is
noted macroscopically as a nodular lesion within the coelomic
cavity of a yellow perch (Perca flavescens). It was classified as

Downloaded from vet.sagepub.com at American College of Veterinary Pathologists on August 31, 2015

Lombardini et al

1009

carcinoma of the bladder involving the urogenital sinus, urinary bladder, and vas deferens.11 The description demonstrates
an invasive, papillary tumor with both squamous and transitional cell components, a feature that is encountered in urinary
bladder neoplasms in humans and other mammals. Because
both the bladder and the urogenital sinus were occupied by the
tumor, the exact site of origin could not be ascertained. In view
of the very close developmental origins of the urinary bladder
and the urogenital sinus (both being lined by endodermal
urothelium), there is little reason to suppose that epithelial neoplasms at these sites should differ from each other. In humans
and other mammals, the neoplasms originating from urothelium of the urinary outflow tract generally include the same
rather narrow range of histological variants, regardless of
whether they are located in renal pelvis, ureter, bladder, or
urethra. This particular case may very well typify urothelial
cancers of the lower urinary tract in fish, but significantly more
specimens would be required before this can be considered as
established.
The RTLA archive contains a single case of a transitional cell
papilloma from a brown bullhead catfish, which is theorized to
have arisen from the renal collecting duct epithelium. The neoplasm is composed of thick arborizing papillary projections lined
by tall columnar cells with indistinct cell borders, supported by a
fine fibrovascular stroma. The neoplastic cells have abundant
eosinophilic cytoplasm, basilar oval nuclei, finely stippled chromatin, and 1 to 2 distinct nucleoli. Frequently, these cells appear
to undergo maturation to form goblet cells and contain a large
clear apical vacuole (Fig. 14).

Conclusions
Review of fish renal lesions underscores the need to accurately
discriminate between infectious processes, hyperplasia, and
neoplasia. Tumors of the urinary tract of fish are uncommon,
and those reported in the literature, be they spontaneous or
experimental examples, are predominantly individual case
reports. Of the many neoplasms and variants described in the
kidneys of higher vertebrates, only a select few have been
reviewed in fish. This is likely due to the greater ease of seeing
disease in terrestrial species as well as the greater scrutiny that
domestic species have received. Considering the significant
superiority in numbers and variety of fish species, there is a
vast body of knowledge waiting to be discovered. The pathobiology of renal tumors of fishes has not been extensively studied. There are only few reports addressing the ultrastructure of
fish neoplasms and equally few cell culture studies.
With the exception of nephroblastomas in Japanese eels and
proximal tubular epithelial neoplasms in Oscars, there does not
appear to be specificity or predilection for any particular tumor
type. Nephroblastomas and kidney primary lymphomas dominate the field, although as each year passes, additional reports
of adenocarcinomas and adenomas appear in the literature,
augmenting the robustness of our understanding and increasing
the depth of our knowledge base. Publication of new findings is
critical to this endeavor.

Acknowledgements
We offer our sincere gratitude to Dr Jeff Wolf for his support in
accessing the RTLA archives; Dr Veronique LePage and her colleagues
at the Fish Pathology Laboratory, Department of Pathobiology, University of Guelph for allowing access to the materials from cases in syngnathids; Dr Wes Baumgartner for examples of disease in catfish and
Gulf killifish; Dr Tabitha Viner and Dr Timothy Walsh for access to the
Smithsonian Zoos pathology archives; and to the myriad dedicated fish
pathologists and clinicians who have donated their material to the
RTLA for the advancement of knowledge and science.

Declaration of Conflicting Interests

The author(s) declared a potential conflict of interest (e.g. a financial relationship with the commercial organizations or products discussed in this
article) as follows: E. D. Lombardini is a Lieutenant Colonel in the US
Army. The opinions or assertions herein are those of the authors and
do not necessarily reflect the view of the Department of the Army or the
Department of Defense.

Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.

Supplemental Material
Supplementary material for this article is available on the Veterinary
Pathology website at http://vet.sagepub.com/supplemental.

References
1. Anders K, Hilger I, Moller H. Lentivirus-like particles in connective tissue tumours of fish from German coastal waters. Dis Aquat
Org. 1991;11:151154.
2. Anders K, Yoshimizu M. Role of viruses in the induction of skin
tumors and tumor-like proliferations of fish. Dis Aquat Org. 1994;
19:215232.
3. Ashley LM. Renal neoplasms of rainbow trout. Bull Wildlife Dis
Assoc. 1967;3:86.
4. Ashley LM. Pathology of fish fed aflatoxins and other antimetabolites. In: Snieszko SF, ed. A Symposium on Diseases of Fishes
and Shellfishes. American Fisheries Society Pub. No. 5. Washington, DC: American Fisheries Society; 1970:366379.
5. Bailey GS, Williams DE, Hendricks JD. Fish models for environmental carcinogenesis: the rainbow trout. Environ Health
Perspect. 1996;104(suppl 1):521.
6. Baumann PC, Harshbarger JC. Decline in liver neoplasms in
wild brown bullhead catfish after coking plant closes and environmental PAHs plummet. Environ Hlth Perspect. 1995;
103(2):168170.
7. Baumann PC, Okihiro MS. Cancer. In: Ostrander GK, ed. The
Laboratory Fish. San Diego, CA: Academic Press; 2000:591616.
8. Blazer VS, Schrank CS. Malignant lymphoma in black bullhead
from Allouez Bay, Superior, Wisconsin, USA. Dis Aquat Organ.
1995;23:229234.
9. Bowser PR, McCoy CP, MacMillan JR. A lymphoproliferative
disorder in a channel catfish, Lctalurus punctatus (Rafinesque).
J Fish Dis. 1985;8:465469.

Downloaded from vet.sagepub.com at American College of Veterinary Pathologists on August 31, 2015

1010

Veterinary Pathology 51(5)

10. Bucke D, Feist SW. Histopathology of some fish tumours from

British waters, including an olfactory glioma in coalfish, Pottachius virens L. J Fish Biol. 1985;27:293305.
11. Budd J, Schroder JD, Dukes KD. Tumors of the yellow perch. In:
Ribelin WE, Migaki G, eds. The Pathology of Fishes. Madison:
University of Wisconsin Press; 1975:895906.
12. Calle PP, McNamara T, Kress Y. Herpesvirus-associated papillomas in koi carp (Cyprinus carpio). J Zoo Wildl Med. 1999;30:
165169.
13. Campbell CE, Gibbs PDL, Schmale MC. Progression of infection
and tumor development in damselfish. Marine Biotechnol. 2001;
3(suppl 1):S107S114.
14. Chandrasekhar K. The urinary bladder of some teleostean
fishes and the incidence of the occurrence of tumours in the
urinary bladder, part I: the urinary bladder. Indian J. Zootomy.
1970;11:115122.
15. Chen CT, Liu KM, Joung SJ. Preliminary report on Taiwans
Whale Shark fishery Elasmobranch. In: Fowler SL, Reed TM,
Dipper FA, eds. Biodiversity, Conservation and Management:
Proceedings of the International Seminar and Workshop, Sabah,
Malaysia; 1997:162166. IUCN, Cambridge, UK.
16. Earnest-Koons KA, Schachte JH Jr, Bowser PR. Lymphosarcoma
in a brook trout. J Wildl Dis. 1997;33:666669.
17. Ehlinger NF. Kidney disease in lake trout complicated by
lymphosarcoma. Prog Fish Cult. 1963;25:37.
18. Fournie JW, Vogelbein WK. Exocrine pancreatic neoplasms in
the mummichog (Fundulus heteroclitus) from a creosotecontaminated site. Toxicol Pathol. 1994;22:237247.
19. Fournie JW, Wolfe MJ, Wolf JC, et al. Diagnostic criteria for proliferative thyroid lesions in bony fishes. Toxicol Pathol. 2005;33:
540551.
20. Furihata M, Suzuki K, Hosoe A, et al. Histopathological study on
Oncorhynchus masou virus disease (OMVD) of cultured rainbow
trout in natural outbreaks and artificial infection. Fish Pathol.
2005;40:161168.
21. Ghittino P, Dalforno S. Nefroblastoma spontaneo in trota iridea
dallevamento (Salmo gairdneri). Riv Ital Piscic Ittiopatol.
1971;6:6972.
22. Ghittino P, Dalforno S, Bignami S, et al. Caso di nefroblastoma in
Anguilla argentina di lagunicoltura. Riv Ital Piscic Ittiopatol.
1985;20:150153.
23. Grizzle JM, Goodwin AE. Neoplasms and related disorders. In:
Leatherland JF, Woo PTK, eds. Fish Diseases and Disorders.
2nd ed. Cambridge, MA: CABI; 2010:1984.
24. Grizzle JM, Buckley-Williams L, Harshbarger JC. Renal adenocarcinoma in Mozambique tilapia, neurofibroma in goldfish and
osteosarcoma from channel catfish from a Puerto Rico hatchery.
J Aquat Anim Health. 1995;7:178183.
25. Groff J. Neoplasia in fishes. Vet Clin North Am Exot Anim Pract.
2004;7:705756.
26. Gumpenberger M, Hochwartner O, Loupal G. Diagnostic imaging
of a renal adenoma in a Red Oscar (Astronotus ocellatus Cuvier,
1829). Vet Radiol Ultrasound. 2004;45:139142.
27. Haddow A, Blake I. Neoplasms in fish: a report of six cases
with a summary of the literature. J Pathol Bacteriol. 1933;
36:4147.

28. Haller RD, Roberts RJ. Dual neoplasia in a specimen of Sarotherodon spilurus spilurus (Gunther) (Tilapia spilurus). J Fish Dis.
1980;3:6366.
29. Hard GC. Comparative oncology, II: nephroblastoma in domesticated and wild animals. In: Pochedly C, Baum ES eds. Wilms
Tumor: Clinical and Biological Manifestations. New York, NY:
Elsevier Science; 1984:91111.
30. Hard GC. Compararative oncology, I: Nephroblastoma in laboratory animals. In: Pochedly C, Baum ES eds. Wilms Tumor:
Clinical and Biological Manifestations. New York, NY: Elsevier
Science; 1984:6989.
31. Hard GC, Noble RL. Occurrence, transplantation and histological
characteristics of nephroblastoma in the Nb hooded rat. Investig
Urol. 1981;18:371378.
32. Hard GC. Differential renal tumor response to N-ethylnitrosourea and dimethylnitrosamine in the Nb rat: Basis for a new
rodent model of nephroblastoma. Carcinogenesis. 1985;6:
15511558.
33. Harshbarger JC, Dawe CJ. Hematopoietic neoplasms in invertebrate and poikilothermic vertebrate animals. In: Dutcher RM,
Chieco-Bianchi L, eds. Unifying Concepts of Leukemia. Basel,
Switzerland: Krager, Basel; 1973:56.
34. Harshbarger JC. Role of the Registry of Tumors in Lower
Animals in the study of environmental carcinogenesis in aquatic
animals. Ann N Y Acad Sci. 1978;29:280289.
35. Hawkins WE, Walker WW, Lytle JS, et al. Carcinogenic effects
of 7,12-dimethylbenz[a]anthracene on the guppy (Poecilia reticulata). Aquat Toxicol. 1989;15:6382.
36. Hayashi S, Furukawa S, Abe M, et al. Lymphoma in a Japanese
Killifish. J Toxicol Pathol. 2008;21:115117.
37. Helfman G, Collette BB, Facey DH, et al. The Diversity of Fishes:
Biology, Evolution, and Ecology. 2nd ed. Oxford, UK: WileyBlackwell; 2009:316.
38. Helmboldt CF, Wyand DC. Nephroblastoma in a striped bass.
J Wildl Dis. 1971;7:162165.
39. Hendricks JD, Scanlan RA, Williams JL, et al. Carcinogenicity of
N methyl N0 nitro N nitrosoguanidine to the livers and kidneys of
rainbow trout (Salmo gairdneri) exposed as embryos. J Natl
Cancer Inst. 1980;64:15111519.
40. Hochwartner O, Loupal G, Wildgoose WH, et al. Occurrence
of spontaneous tumours of the renal proximal tubules in
oscars Astronotus ocellatus. Dis Aquat Org. 2010;89:
185189.
41. Hoole D, Bucke D, Burgess P, et al. Noninfectious diseases. In:
Diseases of Carp and other Cyprinid Fishes. Ames: Iowa State
University Press; 2001:140143.
42. Huizinga HW, Budd J. Nephroblastoma in the smelt, Osmerus
mordax (Mitchell). J Fish Dis. 1983;6:389391.
43. Kent ML, Dawe SC. Experimental transmission of a plasmacytoid leukemia of Chinook salmon, Oncorhynchus tshawytscha.
Cancer Res. 1990;50(17)(suppl):5679S5681S.
44. Kimura I, Kitaori H, Yoshizaki K, et al. Development of tumors in
rainbow trout following embryonic exposure to N nitroso compounds. In: Dawe CJ, Harshbarger JC, Kondo S, Sugimura T,
et al, eds. Phyletic Approaches to Cancer. Tokyo: Japan Scientific
Societies Press; 1981:241252.

Downloaded from vet.sagepub.com at American College of Veterinary Pathologists on August 31, 2015

Lombardini et al

1011

45. Kimura T, Yoshimizu M, Tanaka M. Studies on a new virus

(OMV) from Oncorhynchus masou. 11. Oncogenic nature. Fish
Pathol. 1981;15:149153.
46. Kollinger G, Schwab M, Anders F. Virus-like particles
induced by bromodeoxyuridine in melanoma and neuroblastoma of xiphophorus. J Cancer Res Clin Oncol. 1979;95:
239246.
47. Khudolei VV. Spontaneous and induced neoplasm in aquarium
fishes. Izdatelstvo Nauka Moskva. 1972;74(3):473481.
48. Kottelat M, Britz R, Hui TH, et al. Paedocypris, a new genus of
Southeast Asian cyprinid fish. Proc Roy Soc B. 2006;273:
895899.
49. Kubota SS, Miyazaki T, Egusa S. Color Atlas of Fish Histopathology. Vol 1. Tokyo, Japan: Shin Suisan Shinbun Sha;
1982:1213.
50. Lee BC, Hendricks JD, Bailey GS. Rare renal neoplasms in Salmo
gairdneri exposed to MNNG (N-methyl-N0 -nitro-N-nitrosoguanidine). Dis Aquat Org. 1989;6:105111.
51. LePage V, Dutton CJ, Kummrow M, et al. Neoplasia of captive
yellow sea horses (Hippocampus kuda) and weedy sea dragons
(Phyllopteryx taeniolatus). J Zoo Wildl Med. 2012;43:5058.
52. Lombardini ED, Law M, Lewis BS. Nephroblastoma in two Siamese fighting fish (Betta splendens). Fish Pathol. 2010;45:
137139.
53. Lumsden JS, Marshall S. Sporadic neoplasms of farmed Chinook salmon, Oncorhynchus tshawytscha (Walbaum) from
New Zealand. J Fish Dis. 2003;26:393399.
54. Malins DC, Krahn MM, Myers MS, et al. Toxic chemicals in
sediments and biota from a creosote-polluted harbor: relationships with hepatic neoplasms and other hepatic lesions in
English sole (Parophrys vetulus). Carcinogenesis. 1985;6:
14631469.
55. Maiti S, Alam R, Amos CI, et al. Frequent association of betacatenin and WT1 mutations in Wilms tumor. Cancer Res. 2000;
60:62886292.
56. Masahito P, Ishikawa T, Okamoto N, et al. Nephroblastomas in
the Japanese eel, Anguilla japonica Temminck et Schlegel.
Cancer Res. 1992;52:25752579.
57. Masahito P, Ishikawa T, Sugano H. Fish tumors and their
importance in cancer research. J Cancer Res. 1988;79:545555.
58. Masahito P, Ishikawa T, Takayama S, et al. Gonadal neoplasms in
largemouth bass, Micropterus salmoides and Japanese dace
(ugui), Tribolodon hakonensis. Gann. 1984;75:776783.
59. Mesfin GM, Breech KT. Heritable nephroblastoma (Wilms
tumor) in the Upjohn Sprague Dawley rat. Lab Anim Sci.
1996;46:321326.
60. Meuten DJ, Everitt J, Inskeep W, et al. Histological Classification
of Tumors of the Urinary System of Domestic Animals. Washington, DC: World Health Organization International Histological
Classification of Tumors of Domestic Animals, Second Series
Volume XI, Armed Forces Institute of Pathology, American
Registry of Pathology; 2004.
61. Mikaelian I, de Lafontaine Y, Menard C, et al. Neoplastic and
nonneoplastic hepatic changes in lake whitefish (Coregonus
clupeaformis) from the St. Lawrence River, Quebec, Canada.
Environ Health Perspect. 1998;106:179183.

62. Miyazaki T, Hyakkoku N. A histopathological study on

nephroblastoma of the Japanese eel. Bull Fac Fish Mie Univ.
1987;14:2132.
63. Miyazaki T, Yukako A, Tatsuya K, et al. Lympholeukemia in madai
(Pagrus major) in Japan. Dis Aquat Org. 2000;40:147155.
64. Nakatsuru Y, Minami K, Yoshikawa A, et al. Eel WT1 sequence
and expression in spontaneous nephroblastomas in Japanese eel.
Gene. 2000;245:245251.
65. Nigrelli RF.Tumors and other atypical cell growths in temperate
freshwater fishes of North America: Transactions of the American
Fisheries Society. Ann Arbor, MI: American Fisheries Society;
1954:262289.
66. Odense PH, Logan VH, Baker SR. Spontaneous nephroblastoma
in a rainbow trout. Can J Fish Aquat Sci. 1973;30(4):549551.
67. Oguri M, Sokabe H. Juxtaglomerular cells in the teleost kidneys.
Bull Jpn Soc Sci Fish. 1968;34:882888.
68. Okihiro MS, Hinton DE. Lymphoma in the Japanese Medaka
Oryzias latipes. Dis Aquat Org. 1989;7:7987.
69. Petervary N, Gillette DM, Lewbart GA, et al. A spontaneous neoplasm of the renal collecting ducts in an oscar, Astronotus ocellatus (Cuvier), with comments on similar cases in this species.
J Fish Dis. 1996;4:279281.
70. Pinkney AE, Harshbarger JC, Karouna-Renier NK, et al. Tumor
prevalence and biomarkers of genotoxicity in brown bullhead
(Ameiurus nebulosus) in Chesapeake Bay tributaries. Sci Total
Environ. 2011;410411:248257.
ber einige bei Fischen Beobachtete Geschwulste und
71. Plehn M. U
geschwulstartige Bildungen. Ber Bayer Biol Verssta. 1909;2:
5576.
72. Plehn M. Praktikum der Fischkrankheiten. Stuttgart, Germany: E.
Schweizerbartsche; 1924:424425.
73. Quackenbush SL, Rovnak J, Casey RN, et al. Genetic relationship
of tumor-associated piscine retroviruses. Marine Biotechnol.
2001;3:S088S099.
74. Rehulka J. Spontaneous nephroblastoma in a hatchery rainbow
trout (Oncorhynchus mykiss). Dis Aquat Org. 1992;14:7579.
75. Ruteshouser EC, Robinson SM, Huff V. Wilms tumor genetics: mutations in WT1, WTX, and CTNNB1 account for only about one-third
of tumors. Genes Chromosomes Cancer. 2008;47:461470.
76. Schmale MC, Aman MR, Gill KA. A retrovirus isolated from cell
lines derived from neurofibromas in bicolor damselfish (Pomacentrus partitus). J Gen Virol. 1996;77:11811187.
77. Schlumberger HC, Lucke B. Tumors of fishes, amphibians and
reptiles. Cancer Res. 1948;8:657754.
78. Schmey M. Uber Neubildungen bei Fischen. Frankf Z Pathol.
1911;6:230252.
79. Sharma PM. A rodent model for Wilms tumor: embryonal kidney
neoplasms induced by N-nitroso-N0 -methylurea. Proc Natl Acad
Sci U S A. 1994;91:99319935.
80. Singh BP, Patterson-Kane JC, Redrobe SP, et al. Intrarenal pelvic
nephroblastoma in a meerkat (Suricata suricatta). J Vet Diagn
Invest. 2005;17:623625.
81. Sonstegard R. Lymphosarcoma in muskellunge (Esox masquinongy). In: Ribelin WE, Migaki G, eds. The Pathology of
Fishes. Madison: University of Wisconsin Press; 1975:
907924.

Downloaded from vet.sagepub.com at American College of Veterinary Pathologists on August 31, 2015

1012

Veterinary Pathology 51(5)

82. Sonstegard RA. Environmental carcinogenesis studies in fishes of

the Great Lakes of North America. Ann N Y Acad Sci. 1977;298:
261269.
83. Spitsbergen JM, Tsai H, Reddy A, et al. Neoplasia in zebrafish
(Danio rerio) treated with N-methyl-N0 nitro-N-nitrosoguanidine
by three exposure routes at different developmental stages.
Toxicol Pathol. 2000;28:716725.
84. Stegeman N, Heatley JJ, Rodrigues A, et al. Nephroblastoma in a koi
(Cyprinus carpio). J Exotic Pet Med. 2010;19:298303.
85. Thompson JS. An epizootic of lymphoma in northern pike, Esox
land Islands of Finland. J Fish Dis. 1982;5(1):
lucius L., from the A
111.

86. Tsai HW. Evaluation of zebrafish as a model for carcinogenesis

[dissertation]. Corvallis: Oregon State University; 1997. http://
ir.library.oregonstate.edu/xmlui/handle/1957/28169?showfull
87. Walker R. Virus associated with epidermal hyperplasia in fish.
Natl Cancer Inst Monogr. 1969;31:195207.
88. Williams G.On various fish tumors. In: Proceedings and Transactions of the Liverpool Biological Society. Vol XLV. Liverpool,
UK: C. Tinling & Co; 1931:98108.
89. Williamson HC. On diseases and abnormalities in fishes of the
cod (Gadus), flat fish (Pleuronectes), salmon (Salmo), skate
(Raia), etc. families. Fish Board Scotland Sci Invest. 1911;2:
339.

Downloaded from vet.sagepub.com at American College of Veterinary Pathologists on August 31, 2015