[CANCER RESEARCH 52. 2575-2579. May I. 1992]

Nephroblastomas in the Japanese Eel, Anguilla japónica Temminck and Schlegel1

Prince Masahito, Takatoshi Ishikawa,2 Nobuaki Okamoto, and Haruo Sugano

Department of Experimental Pathology [P. M., T. 1.] and Department of Pathology [H. S.¡,Cancer Institute, Kami-Ikehukuro, Toshima-ku, Tokyo 170, and Departmentof Aquatic Biosciences, Tokyo University of Fisheries, Konan, Minato-ku, Tokyo 108 [N. O.¡,Japan

ABSTRACT

Nephroblastomas were observed in 50 Japanese eel reared at a farmfor 5 to 9 months from 1989 after collection in the wild. The tumors,arising from the trunk kidney near the anus, were noted externally asabdominal swellings and varied in size from 30 to 75 mm in maximumdiameter. Most were elastic, solid, and well encapsulated. Histologically,the nephroblastomas were composed of combinations of three main tissueelements. Spindle- or oval-shaped cells resembling human blastema cellswere observed in most tumors to some larger or smaller degree. Althoughvariation was evident from tumor to tumor, and even within the sametumor, the most common histológica!type was epithelial with formationof alveolar nests, the cells sometimes being arranged in tubular structuressimulating normal renal tubules. A muscle tissue element with distinctcross-striations was also observed. Liver métastaseswere found in onecase. Histological examination of apparently normal kidneys from 100eels revealed one early-stage nephroblastoma.

The cause of these tumors is unclear, although they have been discovered with increasing incidence after the spread of indoor eel culture withraised water temperatures (26-27°C)in Japan. Environmental factor(s)

associated with the new aquaculture method may thus play a role in theirgenesis.

INTRODUCTION

Kidney tumors occur commonly among the teleosts, especially in salmonid fishes, being next in frequency to liver tumors(1,2). However, neoplasms of the kidney seem to be rather rarein the Anguilloid fishes (1-3), with only four previous reportsdocumenting their occurrence (3-6). One adenocarcinoma wasdescribed by Schmey (4) in 1911, one adenoma by Plehn (5) in1924, and one nephroblastoma by Ghittino et al. (6) in 1985 inthe European eel. Anguilla anguilla. A nephroblastoma in oneJapanese eel, Anguilla japónica, was recorded in 1981 in theRegistry of Tumors in Lower Animals (3). More recently, 13nephroblastomas in Japanese eel were reported by Miyazakiand Hyakkoku (7). The purpose of the present paper is todiscuss the features of nephroblastomas in eel and those inhumans on the basis of biological, histológica!, and ultrastructural observations of 50 cases of nephroblastomas in Japaneseeel reared at a farm. Included was the result of a search forearly-stage nephroblastomas in apparently normal Japanese eelkidneys.

MATERIALS AND METHODS

Fifty tumor-bearing Japanese eel (range of lengths, 400-740 mm)and 100 apparently normal Japanese eel (range of lengths, 450-630

mm) were obtained from a farm in Shizuoka Prefecture, Japan, duringthe period from August 1988 to September 1989 (Table 1). Kidneytumors were evident externally in fish which had been reared for 5 to 9months at the farm from elvers caught on the Pacific coast of Shizuoka

Received 7/1/91; accepted 2/25/92.The costs of publication of this article were defrayed in part by the payment

of page charges. This article must therefore be hereby marked advertisement inaccordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1Supported by Grants-in-Aid for Cancer Research from the Ministry of

Education, Science and Culture and Ministry of Health and Welfare, Japan.2To whom requests for reprints should be addressed, at Department of

Pathology, Faculty of Medicine, University of Tokyo, Hongo, Bunkyo-ku, Tokyo113. Japan.

Prefecture in either March or December 1988. Similarly, 100 apparently normal eels (Table 2) reared at the same farm were randomlycollected and transferred to the Cancer Institute. Tubifex was given for1 or 2 weeks at the elver stage. Food was then switched gradually tocod meal (white meal) or sardine meal (brown meal) according togrowth. Daily food intake was determined as 1 or 2% of body weight(1 ton of eel consisted of approximately 4000 fish near the time ofshipment). The eel were kept in circulating and well-oxygenated underground well water ponds covered with vinyl at 26-27°Cthroughout the

year, and new water was at times supplied for partial water change, tomaintain water quality.

All tumor-bearing eels and normal eels used in this study wereimmersed in ice-chilled water for immobilization and sacrificed bydecapitation. The tumorous and normal kidney tissues with otherinternal organs were fixed in 10% neutral formaldehyde solution andembedded in paraffin. Paraffin blocks were sectioned at 3-4 ^m, andsections were stained with hematoxylin and eosin with periodic acid-Schiff and by phosphotungstic acid hematoxylin staining for muscle.

Six kidney tumors were examined by electron microscopy. Immediately after dissection, pieces of tissue were fixed in 2.5% glutaraldehydein 0.1 M phosphate buffer (pH 7.3) for 2 h at 0°C,postfixed in 1%

osmium tetroxide in phosphate buffer, dehydrated by passage througha graded series of concentrations of ethanol, and embedded in Epon.Ultrathin sections were contrasted with uranyl acetate and lead hydroxide and examined with a Hitachi HS-9 electron microscope.

Data on these Japanese eels and their tumors are summarized inTables 1 and 2. Sexes of the fish were determined by histology of theirsex organs. The Japanese eel used in this study demonstrated a male-biased ratio, as earlier described by Matsui (8).

RESULTS

Gross Observations. At autopsy, the kidney tumors wereclearly observed as abdominal swellings near the anus (Fig. 1).They arose from the fused posterior region of the kidney (trunkkidney) and were never observed in the paired anterior kidneyregion (Fig. 2). The tumors varied in size from 30 x 15 x 10mm to 75 x 25 x 15 mm and were all well capsulated (Fig. 3).Most were elastic and solid, although some were soft. Their cutsurfaces were grayish-white. Some tumors had large cysts.Normal dark brown kidney tissues could sometimes be identified at the periphery of the tumor (Fig. 4).

Histological Findings. Histologically, tumor cells constitutedmost of the tissue masses, with normal kidney tissues occasionally being seen embedded as minor components. Most commonly tumors were composed of epithelial and muscular elements in different amounts, varying from focus to focus or fromcase to case. In some parts of tumors, irregular tubular structures with cuboidal or columnar epithelial cells resemblingnormal renal tubules were seen, and some of these were baso-philic and others were eosinophilic. Epithelial cell nests weresurrounded by proliferating blastema cells (Fig. 5). Primitiveglomeruli were sometimes found within spaces lined by flattened cells somewhat similar to the parietal epithelium ofBowman's capsule (Fig. 6). In 38 of 50 tumor cases (76%),

dark-stained spindle-shaped or oval cells resembling humanblastema cells were observed around the tubules (Fig. 7). Strictlyspeaking, blastema cells were observed in most tumors to somelarger or smaller degree. However, to clarify the histológica!

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NEPHROBLASTOMAS IN THE JAPANESE EEL

Table 1 Histological type of Japanese eel nephroblastomas

Predominating histologicalcomponentNumber

of tumors50Renaltubules(%)38

(76)No.

of tumors withblastema cells

(%)38

(76)Skeletal

muscles(%)20

(40)Number

ofmétastases

(organ)1

(liver)

type, the predominating component was taken into account(Table 1). In 2 of these 38 cases (5%), these spindle-shapedcells predominated and there were no tubular structures. In 20of 50 tumor cases (40%), single or multiple round islands ofmuscle tissue intermingled with tumorous renal tubules, orblastema-like cells were found. In some of the tumors there wasan indication of transition from blastema cells to striated muscleforms, suggesting the possibility that the latter may have derivedfrom the blastemal stem cells. In four lesions, muscle tissueelements occupied the majority of the tumor. Cross-striation,characteristic of skeletal muscle, was observed at high magnification in sections stained by phosphotungstic acid hematox-ylin (Fig. 8). These muscles were surrounded by fiber bundles.In a few cases, lymphoid tissues were seen within tumors as innormal kidney. One case of 50 demonstrated distinct distantmétastasesto the liver, with multiple metastatic foci resemblingrenal tubular structures admixed with blastema cells distributedthroughout the organ (Fig. 9). The primary tumor of this case,however, was composed mostly of muscular elements, withepithelial cell differentiation mainly at the periphery. From thepathological features, all kidney tumors were diagnosed asnephroblastomas.

One hundred kidneys from 100 eels apparently normal fromgross appearance were also examined for tumor development.One nephroblastoma, measuring 7.2 x 3.5 mm, was microscopically discovered (Fig. 10). Histologically, this tumor was composed of basophilic, less differentiated epithelial cells formingtubular structures.

Electron Microscope Findings. Ultrastructural examinationof the blastemal cells demonstrated cells with a high nucleocy-toplasmic ratio and sparse cytoplasmic organelles (Fig. 11). Insome parts of tumors showing differentiation toward musclecell elements histologically, Z bands were discerned in theabundant bundles of myofilaments under the electron microscope. Small, dark, rounded cells indicative of transition fromblast cells had abortive striated muscles in their cytoplasm (Fig.12). The muscle tissue also contained abundant glycogen granules. Electron microscopy of areas corresponding to epithelial-type tubular structures revealed some tumorous renal tubularcells to be ciliated (Fig. 12), and these cilia contained the normal9 + 2 complex of 9 doublets of tubules arranged in a circlearound 2 central pairs of tubules (not shown in the figure).These tubular cells also had numerous or a few microvilli. Intypical cases, these microvilli formed a brush border along thetubular lumen. Many round or oval mitochondria and well-developed rough endoplasmic reticulum elements were observed in the tumorous tubular cells.

DISCUSSION

In 50 cases of nephroblastomas observed in wild-born Japanese eel reared on a farm, all developed in the posterior part ofthe kidney (trunk kidney), which is functional, with abundantnephrons. The paired long, slender kidneys extend anteriorlyfrom the trunk kidney. In the eel the anterior portion of thekidney is poorly developed (9). Although reptiles, birds, and

mammals are characterized by the development of a posteriorkidney (metanephros) which is functional throughout adult life(10), the mesonephros has a chiefly renal function in adult fish(9). In Anguilloid fishes, the pronephros is a vestigial organ inelvers (11). The mesonephros has the chief renal functions inthe elvers (11) and adults (9, 11). Therefore, the results wouldsuggest that eel nephroblastomas originate from the mesonephros. However, in humans nephroblastomas were regarded toarise from the metanephric blastema (12). Histologically, thefinding that eel tumor tissues included blastema-like cells, renaltubular cells, and skeletal muscle cells or stromal cells suggestsessential similarities with nephroblastomas in humans (12). Ahistopathological study on 13 cases of eel tumor was made byMiyazaki and Hyakkoku (7). In our cases of eel nephroblastomas, Z bands were found in the muscle fibers by electronmicroscopy, as in human nephroblastomas (12). There havebeen no reports concerning the presence of striated muscle innephroblastomas from fishes other than the Japanese eel (6,13, 14). But the presence of smooth muscle was not clear in theeel nephroblastomas, as mentioned by Miyazaki and Hyakkoku(7). The existence of cartilage has been reported for nephroblastomas in one Japanese eel (7), one European eel (6), onestriped bass, Morone saxatilis (13), and one rainbow smelt,Osmerus mordaks (14), as well as in humans (12). Electronmicroscopic observations revealed that the cilia have the 9 + 2pattern in the tumorous tubular cells of eel nephroblastomas.In the normal adult fish kidney, cilia are always seen in theproximal tubules (15). Ito and Johnson (16) reported that ciliaformation was observed in 8 of the 23 Wilms' tumors and

occasionally in normally developing proximal tubules. The ciliaformation in the Wilms' tumors was regarded as an expression

of embryonal character of the tumors. Human nephroblastomasoften metastasize, and the histological appearance of metastaticlesions is sometimes different from that of the primary tumor(12). In one eel nephroblastoma case where hepatic métastaseswere found, the métastasesmarkedly differed in histologicaltype from the main primary tumor component. Thus the histological and ultrastructural findings showed a striking similarity between nephroblastoma lesions in both humans and theJapanese eel. However, it must be borne in mind that embryo-logically the mesonephros is the functional kidney in fish (17).

In humans, nephroblastomas develop in children or infants(12). The present nephroblastomas, in contrast, were observedin fish which had been maintained in a pond for 5 to 9 monthsafter collection from the wild as elvers. These elvers are believedto arrive at the Japanese coast by swimming from the Luzonarea in the Philippines within 6 months after hatching (18).Therefore, the Japanese eel nephroblastomas can be regardedas developing within approximately 1 year. Thus while onsetage seems to correspond to the period of infancy, eel adultsmay also be affected, and nephroblastomas in fish are not alwaysembryonal tumors, as in humans (17).

In Japanese eel nephroblastomas, genetic influences mayhave been a contributory factor, as in human nephroblastomas,since these fish are considered to be relatively homogeneous interms of genetic background (19). It must be pointed out,however, that the incidence of nephroblastomas has clearlyincreased with the spread of indoor eel farming using circulating

Table 2 Surrey ofnephrohlastoma development in apparently normal kidneys

No. offishFish total length

(mm)Feeding period

(months)No. of tumor-

bearing fish (%)

100 450-630 6-9 MD

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Fig. 1. Eel with rii-ipinni-!.••.inni..',demonstrating abdominal swellings in the anal region.xO.5.

Fig. 2. Normal eel kidney showing the posterior portion of the kidney (trunk kidney, arrowhead) and the paired anterior kidneys (arrows).x 1.0.

Fig. 3. Nephroblastoma arising from (hetrunk kidney, x 1.3.

Fig. 4. Cut surface of an eel ncphroblastoma.Normal dark brown kidney ean be identified atthe periphery, x 1.5.

Fig. 5. Microscopic overview of nephroblas-toma showing epithelial cell nests and surrounding blastema cells. H&E. x 90.

Fig. 6. Section of an eel nephroblastoma demonstrating a blastema aggregate and nests oftubular differentiation. The glomcrulor profilesare not necessarily within tubules but withinepithelium-lined spaces possibly equivalent toBowman's capsules. H&E, X 90.

water adjusted to 25-26°C and dense population culture con

ditions. Therefore, environmental factors may also be responsible. First of all, infection with viruses can be considered asone possible etiological factor. Nephroblastomas can be inducedin chicken by the chicken retrovirus, NK 24, isolated from achicken nephroblastoma (20) and a Birnavirus group-type viruswas isolated from the internal organs of Japanese eel withnephroblastomas by Ueno et al. (21) in 1984. However, theyfailed to induce nephroblastomas in eel following injection ofthe virus (21).

The possibility of genesis of carcinogens or promoters in thewaters cannot be excluded. An maximum of 6 ppm nitrous acidwas actually measured in eel farm culture water (22), a relativelyhigh level compared to well water (maximum 0.08 ppm) fromthe same region (22). According to Yamagata and Niwa (23),nitrous oxide, at concentrations of 1, 3, or 10 ppm, causedneither acute nor chronic toxicity in Japanese eels, but 30 ppmcaused growth inhibition and hypochromemia. While the car-cinogenicity of sodium nitrite itself has not been clarified, thischemical can act as a precursor for carcinogenic <Y-nitrosocompounds in combination with secondary amines in food orin the body (24). This may be of relevance, since Ashley (25)succeeded in inducing nephroblastomas in the adult rainbowtrout. Oncorhynchus mykiss, using dimethylnitrosamine. Criccoet al. (26) failed to produce nephroblastomas with dimethylnitrosamine but confirmed that dimethylnitrosamine was a potent

liver carcinogen in rainbow trout.In the European eel, the formation of new nephrons occurs

following injection of mammalian prolactin (27). A single injection of 500 mg/kg hexachlorobutadiene also induces newnephron development in adult goldfish kidneys (28). This potential for differentiation during the adult stage would suggestthat low levels of carcinogens in the aquatic environment mayinitiate nephroblastomas even in adult fish. The present resultsare in line with the report of Chinino et al. (6) of a nephroblastoma occurring in a silver European eel, judged to be an adultfrom its color and length.

In ponds covered with vinyl, the warm water adjusted to 26-27°Cmay enhance carcinogenic or nephrotoxic effects. For

example, Kyono and Egami (29) noted that liver tumorigenesisin the medaka, Oryzias latipes, was accelerated when the temperature was high. However, the reason why nephroblastomasin the Japanese eel have increased with the spread of indoor eelculture remains obscure. A number of laboratories have recentlyreported that activation of oncogenes may be essential for theinduction of tumors in mammals (30). and fish have proved tobe no exception (31, 32). Phylogenetic studies have revealedthat oncogenes are widely distributed in various organisms,including fish (32-37). Interest is now being concentrated onwhether eel nephroblastoma development may also be regulatedby antioncogenes as isolated from human nephroblastomas byRose et al. (38). The eel nephroblastomas could be a potentially

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NEPHROBLASTOMAS IN THE JAPANESE EEL

.:W-/S

Fig. 7. Section of a nephroblastoma illustrating blastema cells surrounding tubular structure.H&E. x 200.

Fig. 8. Section of a nephroblastoma in an eelshowing muscle tissue elements with distinctstriations. Stained by phosphotungstic acid he-matoxylin. x 900.

Fig. 9. Section of the liver of an eel containinga metastatic focus with features of renal tubuliadmixed with blastema cells. H&E, x 200.

Fig. 10. Section of an apparently normal kidney containing a microscopic nephroblastoma(arrows). H&E, x 100.

Fig. 11. Electron micrograph of an eel nephroblastoma demonstrating the blastema! cells, x7,500.

Fig. 12. Electron micrograph of an eel nephroblastoma illustrating tumors tubular epithelialcells with cilia protruding into the lumen andabortive striated muscle cells, x 7.500.

important model for helping to elucidate the molecular patho- 6genesis of Wilms's tumors.

7.

ACKNOWLEDGMENTS 8

We are grateful to Hironori Murayama and Kiyomi Kohyama fortechnical assistance. We thank Keiko Isahaya for help in preparationof the manuscript.

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1992;52:2575-2579. Cancer Res   Prince Masahito, Takatoshi Ishikawa, Nobuaki Okamoto, et al.   Temminck and Schlegel

Anguilla japonicaNephroblastomas in the Japanese Eel,

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