Fish Urinary Tract Tumors

Nondomestic, Exotic, Wildlife and Zoo Animals–Review

Neoplasms of the Urinary Tract in Fish

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

AbstractThe veterinary literature contains scattered reports of primary tumors of the urinary tract of fish, dating back to 1906. Many of themore recent reports have been described in association with the Registry of Tumors in Lower Animals, and most of the spontaneousneoplasms of the kidney and urinary bladder are single case reports. In rare instances, such as described in nephroblastomas ofJapanese eels and tubular adenomas/adenocarcinomas of Oscars, there is suggestion of a genetic predisposition of certain popu-lations 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 thosecase reports of renal lymphoma and plasmacytic leukemia are addressed within the context of this review.

Keywordsfish 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 verte-

brates, which further consists of the extant class Chon-

drichthyes 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 patho-

geneses, 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 inter-

actions 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

Institute’s 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 find-

ings 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 gener-

ous 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

1 Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand2 Private Consultant, Tairua, New Zealand3 Department of Pathology, George Washington University Medical Center,

Washington, DC, USA

Corresponding Author:

E. D. Lombardini, Armed Forces Research Institute of Medical Sciences,

USAMC-AFRIMS, APO AP, 96546.

Email: [email protected]

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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 lym-

phoma and plasmacytic leukemia will be addressed within the

context of this review.

Primary renal neoplasia in higher vertebrates is predomi-

nantly split into the 2 most common forms, being nephroblasto-

mas 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 indi-

vidual 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 var-

ious 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- N-

nitrosoguanidine (MNNG), dihydroepiandrosterone (DHEA),

multiple aflatoxins, nitrosamines, and polynuclear aromatic

hydrocarbon (PAH), and while these compounds have been pri-

marily 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 heterocli-

tus)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 adeno-

virus.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 out-

breaks 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 carcino-

genesis, 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 (Oncor-

hynchus keta), Coho salmon (Oncorhynchus kisutch), and

rainbow trout, but the primary tumors are typically found

within cutaneous tissues.45 The virus causes age- and isolate-

correlated 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 tumor-

associated herpesviruses that result in systemic disease include

Herpesvirus cyprini, herpesvirus of Japanese flounder, and epi-

zootic 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 Lin-

dau (VHL) tumor suppressor gene, while the Eker rat is an ani-

mal 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 spon-

taneous 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

Lombardini et al 1001



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 tumor-

igenesis. 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 mini-

mal overlap between the genes involvement.55,75 Furthermore,

rat models have been developed using strains of Sprague-

Dawley 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 repre-

sent 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 hakonen-

sis),58 smelt,42 Siamese fighting fish (Betta splendens),52 sock-

eye 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 corre-

lation 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 Further-

more, studies examining the environmental impact of MAM

have produced neoplastic transformation in several visceral

organs in a variety of species, including guppies (Poecilia reti-

culata), zebrafish (Danio rerio), and medaka (Oryzias latipes).

The predominant populations of neoplasms were concentrated

within the liver of each individual species, but medaka pro-

duced 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 ver-

tebral 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-cm-

long 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 ori-

gin 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 presenta-

tion, 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 develop-

ment of the anterior pronephros and the posterior opisthone-

phros, 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 overwhel-

mingly 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 consis-

tent with the traditional triphasic histopathological appearance

of the tumors in humans. The 3 diagnostic criteria include some

combination of blastemal, epithelial, and mesenchymal ele-

ments, 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, sur-

rounding, 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

Bowman’s capsule (Fig. 2). The blastemal population is char-

acterized 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 ele-

ment 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 nephroblas-

toma in 4 other species of the salmonid family besides the

1002 Veterinary Pathology 51(5)



rainbow trout—namely, brown trout (Salmo trutta), Coho sal-

mon, Chinook salmon (Oncorhynchus tshawytscha), and chum

salmon. In the former 3 species, the tumors histologically fell

within the range expressed by the rainbow trout nephroblasto-

mas, with primitive glomerulus formation in the brown trout

specimen, loose sheets of blastema with minimal epithelial

differentiation in the Chinook salmon, and squamoid differen-

tiation 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 addi-

tion 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 sur-

rounded by contiguous areas of blastema and tubules (Fig. 4).

Figure 1. Kidney; Chinook salmon (Oncorhynchus tshawytscha). Markedly replacing and effacing the kidney and obscuring the coelomic cavity is adensely cellular neoplasm (asterisk). Hematoxylin and eosin (HE). Figure 2. Kidney; Chinook salmon (O. tshawytscha). Piscine nephroblastomasare composed of the same 3 neoplastic cell populations described in higher vertebrates. This photomicrograph demonstrates the epithelial cellsforming disorganized tubules and rare primitive glomeruli surrounded by swaths of blastema characterized by dense swaths of small polygonalcells. HE. Figure 3. Nephroblastoma; Siamese fighting fish (Betta splendens). In addition to the epithelial and blastemal component, fish nephro-blastomas 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 withprominent coalescing islands of cartilage. HE. Figure 5. Kidney; Oscar (Astronotus ocellatus). Replacing the renal parenchyma is a renal adenomacomposed of epithelial cells forming papillary projections into cystic regions. HE. Figure 6. Coelom cross section; yellow seahorse (Hippocam-pus kuda). Obscuring and effacing the coelomic cavity and replacing the viscera is a multinodular, expansile neoplasm diagnosed as a renal ade-noma. HE. Figure 7. Kidney; polka dot sting ray (Potamotrygon leopoldi). Replacing and mildly compressing the renal parenchyma is a highlyvascular renal adenoma (arrows). HE. Figure 8. Kidney; Polka dot sting ray (P. leopoldi). Replacing the renal parenchyma is a neoplasm composedof densely packed polygonal cells with abundant eosinophilic, finely granular cytoplasm. At high magnification, there is approximately 1 mitoticfigure 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 adeno-carcinoma due to regions of desmoplasia and regional anaplasia of neoplastic cells. HE.




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 rain-

bow 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 dis-

played 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 struc-

tures, 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 typi-

cal elongated myotubes. The silver eel tumor is described as hav-

ing 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 strik-

ing 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 differentia-

tion 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 major-

ity of human nephroblastomas) to neoplasms consisting of

blastema, differentiated into tubule profiles, and neoplastic sec-

ondary mesenchyme in the form of sarcoma cells and striated

muscle. It is this potential for biphasic differentiation into neo-

plastic 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 experi-

mentally 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 nephroblasto-

mas 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 experimen-

tally induced nephroblastomas in salmonids and their varia-

tions with respect to the predominance of certain histological

features are the same as in the spontaneously occurring neo-

plasms 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 car-

cinomas 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 corre-

lates. 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 (Oreochro-

mis mossambicus),24 and yellow or spotted seahorses (Hippo-

campus 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 refer-

ences 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 neo-

plasms, 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, signifi-

cantly effaced the renal parenchyma (Fig. 5). While determined

to be locally expansile and potentially regionally aggressive,




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 lit-

erature 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 neo-

plastic 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, includ-

ing examples in a tilapia (Sarotherodon spilurus).28 Chinook sal-

mon,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 (Hippocam-

pus abdominalis), and weedy sea dragons (Phyllopteryx taenio-

latus). A total of 7 neoplasms and 2 lesions described as

neoplastic-like were identified, to include a renal adenocarci-

noma, 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 sea-

horse 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 leo-

poldi) 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, Mozambi-

que tilapia (Oreochromis mossambicus), winter flounder, and

Chinook salmon. Each of these 5 tumors consisted of a popula-

tion 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 epithe-

lium usually having eosinophilic cytoplasm. The cells were

polarized, with basally disposed vesicular nuclei, each contain-

ing 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 par-

enchyma was evident. Mitotic figures were found particularly

at the invasive periphery of the tumor.




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 preexist-

ing 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. Histopatholo-

gically, 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. Microscopi-

cally, the mass was described as being a poorly encapsulated

neoplasm that effaced and replaced the preexisting renal par-

enchyma. 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

Figure 10. Kidney; Mosambique tilapia (Oreochromis mossambicus). The renal parenchyma is effaced by an expansile neoplasm composed ofpolygonal cells arranged in disorganized tubules supported by a fine fibrovascular stroma. Hematoxylin and eosin (HE). Figure 11. Kidney; Chi-nook salmon (Oncorhynchus tshawytscha). Invading the interstitium, separating and replacing renal elements is an adenocarcinoma composed oftubules and papillary projections lined by multiple layers of neoplastic polygonal cells. HE. Figure 12. Kidney; winter flounder (Pseudopleuro-nectes 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 infil-trated by neoplastic lymphocytes. HE. Figure 14. Kidney; brown bullhead catfish (Ameiurus nebulosus). Multifocally, the neoplastic cells of thetransitional cell papilloma undergo maturation to a goblet cell phenotype characterized by a large apical vacuole. HE.




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 con-

sisted 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 concentra-

tions 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 convo-

luted 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 nota-

ble difference in response to exposure to treatment with MNNG

in comparison with trout. Zebrafish exposed during develop-

ment to MNNG have developed both renal adenomas and

adenocarcinomas but do not develop the typical nephroblasto-

mas 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 spe-

cies 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 exag-

gerated descriptions of both mononuclear cell nephritis and

lymphoma being maintained within the earlier published liter-

ature. 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 kid-

ney 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 compres-

sing 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 anisocyto-

sis 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 sig-

nificant mortality in multiple production sites in British Colum-

bia 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 kid-

neys 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 consist-

ing of expansion of the glomeruli by leukocytes with concur-

rent thickened basement membranes and hyperplasia of the

Bowman’s 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 histopathologi-

cally 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 leuke-

mia 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




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 char-

acterized by sheets of round cells with moderate pleomorph-

ism, hyperchromatic nuclei, and a markedly increased mitotic

index. These cases were interesting in that they were animals

having concurrent severe mixed bacterial infections and necro-

tizing 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 concur-

rent 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 dis-

tinct 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 essen-

tially 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 col-

lecting 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 epithe-

lium 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 sup-

ported 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 character-

istic 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, char-

acterized by partially encapsulated, densely cellular masses that

replaced a significant portion of the renal parenchyma. Neoplas-

tic cells were polygonal, arranged in variably sized tubules,

which occasionally were markedly dilated and cystic. Multifo-

cally, 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 meta-

plastic 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 animal’s 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 mor-

hua).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 descrip-

tions 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




carcinoma of the bladder involving the urogenital sinus, urin-

ary bladder, and vas deferens.11 The description demonstrates

an invasive, papillary tumor with both squamous and transi-

tional 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 neo-

plasms at these sites should differ from each other. In humans

and other mammals, the neoplasms originating from urothe-

lium 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 neo-

plasm 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 chro-

matin, 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 patho-

biology of renal tumors of fishes has not been extensively stud-

ied. 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 domi-

nate 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, Univer-

sity of Guelph for allowing access to the materials from cases in syng-

nathids; Dr Wes Baumgartner for examples of disease in catfish and

Gulf killifish; Dr Tabitha Viner and Dr Timothy Walsh for access to the

Smithsonian Zoo’s 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 rela-

tionship 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, author-

ship, 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.

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Fish Urinary Tract Tumors

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