Spontaneous tumours in tree shrews (Tupaia belangeri): Population studies

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J. (]omp. l'ath. 1998 Vol. 118, 301 316

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Spontaneous Tumours in Tree Shrews (Tupaia belangeri): Population Studies M. Brack

Department o/Pathology, German Primate Centre, I~llnerweg 4, D-37077 GO'ttingen, Germany Summary In a necropsy series at the German Primate Centre, 63 o[" 1132 tree shrews were found to have tumours. The youngest afflicted animal was <6 months old, but the incidence of tumours increased strikingly beyond 2 years of" age; of 17 animals aged >8 years, no less than 14 (82"4%) were affected. The sites of neoplasia were the genital system (22 cases), haematopoietic system (18 cases of malignant lymphoma, many involving the digestive tract), lungs (14 cases), integument (five cases), digestive tract (three cases other than those with malignant lymphoma) and urinary bladder (one case). 9 1998 W.B. Saunders CompanyI,imitcd

Introduction Tree shrews are valuable experimental animals, particularly in stress-related research. Their taxonomical position lies between insectivores and prosimian primates and they are therefore more closely related t h a n laboratory rodents to man. Tree shrews reach sexual maturity at approximately 4 months of age, and their life expectancy in captivity ranges from 8 to 10 years, or occasionally longer (Jones, 1980; Bever and Sprankel, 1986; Collins et al., 1987). Male tree shrews possess a well developed scent gland (jugulo-sternal gland, gular gland), which takes the form of a circumscribed, specialized area of the presternal skin. So far, 23 tuinours have been reported in tree shrews (Elliot et al., 1966; Efli'on et al., 1977; Fltigel, 1981; Benirschke, 1983; Bever and Sprankel, 1986; Lowenstine, 1986; Brack, 1988a,b, 1992). Most previous reports contain no precise information on age, and only one (Elliot et al., 1966) makes any reference to the incidence o f t u m o u r s in this species. In this paper, 63 tumours occurring in the tree shrew colony of the G e r m a n Primate Centre (GPC) are described, including those already reported by Brack (1988a,b, 1992).

Materials and Methods

Animals The tree shrew breeding colony of the GPC has been maintained at approximately 140 animals since 1983. The housing and feeding conditions have been described previously (Fuchs and Schumacher, 1990). In summary, the animals are housed indoors, behind an air-conditioned barrier system, in stainless steel mesh cages, with sawdust bedding beneath but not within the cages. They are f~d commercially available pellets enriched with vitamins, and seasonal fruits. 0021 9975/98/040301 + 16 $12.00/0

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Regulations at the GPC require the routine necropsy of all animals that die or are killed. Between 1983 and 1996, 1132 tree shrews were examined post mortem, disregarding severely mutilated or decomposed animals and animals of unknown age. Tumours of the CNS were excluded from the study because, as a rule, the brains were removed before the carcasses were forwarded for necropsy.

Post-mortem Procedures At necropsy, the pelvic, abdominal and thoracic organs, as well as visibly abnormal parts of other organs, were fixed in 10% neutral buffered formalin and embedded in paraffin wax. Sections (3 ktm) were cut and stained with haematoxylin and eosin (HE) and trichrome (Masson-Goldner). Resin-embedded tissues were used to prepare thin sections (1 gin), which were stained with toluidine blue and methenamine silver (Movat). Other staining methods (periodic acid-Schiff [PAS], Turnbull's blue, alcian blue, lectin stains) were employed as required. Statistical Analysis The significance of comparisons of percentages was determined by ~2 tests (CavalliSforza, 1969). Results

O f the 1132 tree shrews, 63 (5"6%) had tumours. Table 1 gives details of age, sex and tumour type for each affected animal. The Kiel classification (Lennert, 1981) was used for lymphomas. The classification used by Spencer (1977) was applied to lung tumours and that used by Lever and Schaumburg-Lever (1990) to skin tumours. For other tumours the Armed Forces Institute of Pathology classification (1967 1990) was used. With the exception of animals in the youngest age group (<4 months) all age groups were affected, but Table 2 shows the steep, almost linear, increase of tumour incidence beyond 2 years of age. The primary tumour sites are shown in Table 3. Tumours of the genital system were the most common (22 cases), followed by those of the haematopoietic system (malignant lymphomas; 18 cases) and respiratory tract (14 cases). Tumours in other sites were less common.

Tumours of the Male Genital System The 15 tumours were exclusively testicular, predominantly of Leydig cell origin (10 cases). O f the 10 Leydig cell tumours, nine were unilateral (left testis only) and one bilateral. Leydig cell tumours usually caused testicular enlargement, with whitish discoloration. Histologically, they consisted of solid to trabecular growth of large, slightly eosinophilic cells with round to ovoid nuclei of variable size, well-defined cellular borders and abundant vacuolar foamy cytoplasm (Fig. 1). Reinke crystalloids could not be identified by light microscopy. Sertoli-cell tumours (cases 2041 and 2035), both of which developed in the right testis only, were characterized by a somewhat radial growth of cells with ill-defined cytoplasmic borders, globoid nuclei of regular size, and large, fattype vacuoles in the slightly eosinophilic cytoplasm.

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M. Brack Table 2 A g e d i s t r i b u t i o n of t u m o u r s

Age group (years)

Number of animals

0 0.3 0.3 1 1-2 2 3 3-4 4 5 5 6 6 7 7 8 >8 Total

Number (and %) of animals with turnouts

509 356 11l 42 26 19 22 16 14 17

0 (0) 4 (1.1) 2 (1.8) 3 (7.1) 5 (19'2) 6 (31.6) 11 (50) 9 (56-3) 9 (64.3) 14 (82.4)

1132

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Table 3 Primary tumour sites

Tumour sites

Genital system Haematopoietic system Respiratory system Integument Gastrointestinal tract* Urinary bladder

Number of animat~ with tumours

Percentage of total number of animals (1132) in survey

Percentage of total number of tumours (63)

22 18 14 5 3 1

1"9 1"6 1"2 0-4 0"3 0"08

34"9 28"6 22'2 7"9 4'7 1'6

* Excluding malignant lymphomas (classified under "Haematopoietic system"), many of which occurred in the gastrointestinal tract.

Two 6-year-old animals (1740 and 4357) had unilateral seminomas (one right side, one left), consisting of trabecular growth of regularly sized, polyhedral, eosinophilic cells. T h e trabeculae were separated by a delicate fibrous stroma (Fig. 2). The tumour cell nuclei were normochromic, globular, and uniform in size and shape; mitotic figures were lacking. One suspected neoplasm proved to be a tumour-like hamartoma, with adrenal cortical tissue misplaced between the tunica alba and the testicular parenchyma.

Tumours of the Female Genital System and Mammary Glands Mammary tumours were found in five animals (1419, 1726, 1939, 2974 and 3416), and ovarian tumours in two (1931 and 3823). All mammary tumours were classified as intraductal carcinomas (Fig. 3), in one case (1726) of the comedo type. The intraductal carcinomas were characterized by their tendency to metastasize or show primary multifocal development within the affected glands. Both ovarian tumours were cystic to papillary adenocarcinomas, consisting of cuboid to columnar epithelia with a papillary growth pattern (Fig. 4),

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L e y d i g col! i m m m r (cast" no. 3(lilt;). T o l u i d i n c blue. x 400.

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Intraductal m a m m a r y adenocarcinoma (case no. 2974). HE. x 63.

Fig. 4.

Ovarian cystic-papillary adenocarcinoma (case no. 3823); arrows indicate brush border. Lectin stain, x 250.

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309

Pulmonary adenocarcinoma; arrows indicate goblet ceils. PAS. x 100.

supported by a delicate fibrous stroma. In one animal (1931) the tumour had metastasized to the mesenteric lymph nodes and, probably transabdominally, to the liver capsule.

Malignant Lymphomas Malignant lymphomas occurred mainly in the gastrointestinal tract and mesenteric lymph nodes, and not infrequently in the spleen and kidney. (The renal tissues of tree shrews possess small subpelvic lymphoid follicles.) In most cases the malignant lymphomas were composed of small to mediumsized lymphocyte-type cells, with occasional large blast cells. The blast cell nuclei were round to ovoid and contained one or more marginally located nucleoli, thus corresponding to centroblast-type malignant lymphomas. In one case (2182), most of the large blast cells had bizarre, cleaved or contorted nuclei. In a further case (1081), small germinal centres were surrounded by wide coronas of small lymphocytes and numerous "starry sky cells", as in human mantle-cell lymphomas. All the lymphomas were found in adult animals, especially older or senile ones.

Tumours of the Respiralory System Lung tumours, which were tbund in 14 tree shrews, occurred first in 1993 and with an increasing frequency in the following years. The youngest animals affected (3428 and 3559) were less than one year old at the time of necropsy, and males were more commonly affected than females (P<0"05). Twelve of

310

Fig. 6.

M. Brack

Adenocarcinoma ofjugulo-sternal gland (case no. 1740).

the pulmonary tumours were adenomas or adenocarcinomas (Fig. 5), originating from the terminal bronchi and bronchioli, as indicated by the presence of PAS-positive goblet cells in the tumour-cell complexes. Two tumours were squamous cell carcinomas. Both the adenocarcinomas and the squamous cell carcinomas developed multifocally and extended by invasive growth into adjacent alveoli, but metastasis into the regional (mediastinal) lymph nodes or beyond was observed in only two cases (3006 and 4357). Other Tumours

The most c o m m o n tumours of the skin and appendages were adenocarcinomas of the jugulo-sternal glands (animals 1672, 1740 and 1864) (Fig. 6). These arose predominantly from the sebaceous gland portions of the jugulo-sternal glands; all had invasive growth characteristics, and in two cases metastasis to the regional lymph nodes (Fig. 7) was observed. Other tumours of the integument were a poorly differentiated sarcoma of the nasal subcutis (Fig. 8) and a sarcoma of the m a m m a r y skin (animal 3328). Neoplasms of the gastrointestinal tract (other than malignant lymphomas) consisted of two cases (1685 and 4084) of multiple recto-anal papilloma and one case (2363) of oesophageal carcinoma. One of the recto-anal papillomas extended through the anal orifice, but the other was confined to the rectoanal canal; in both cases the tumours were composed of parakeratotic (and in parts also acanthotic) squamous epithelia of either exophytic or endophytic growth pattern. The basal cells of the endophytic papillomas in case 4084 had proliferated to form long, basal cell carcinoma-like strands or rows (Fig.

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Sebaceous gland type a d e n o m a ofjugulo-sternal gland (ease no. 1672). Movat. x 400.

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Fig. 9.

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Oesophageal squamous cell carcinoma (case no. 2363). Toluidine blue. x 400.

T u m o u r s in Tree S h r e w s

313

9). The oesophageal carcinoma was of an anaplastic squamous cell type (Fig. 10), consisting of polygonal cells of varying size, with distinct cytoplasmic borders. The tumour had metastasized to the spleen. One tumour of the urinary bladder was seen in an 11-month-old female (1147). It was characterized by a massive downgrowth of ill-defined strands or clusters of a highly anaplastic urothelium into the lamina submucosa. The neoplastic growth was accompanied by a moderate to heavy, predominantly lymphocytic, inflammatory response. The tumour was recorded as a diffusely invasive carcinoma. Discussion

The tumour incidence of 5"6% in trec shrews aged <6 months to >8 years contrasts with the paucity of previous reports of tumours in this species and with opinions concerning the rarity of tumours in closely related non-human primates (Griesemer, 1976). In the latter, the incidence ranged from <1% (Jungherr, 1963; Chesney 1972; Weber and Greefl, 1973) to as much as 3"5% (Snyder and Ratcliffe, 1963; Kronberger and Rittenbach, 1968; Seibold and Wolf, 1973; Schappel el al., 1980). As in man and non-human primates, the tree shrew tumour incidence increased with age from 0% in animals below the age of 4 months to >80% in senile animals of more than 8 years of age. In man, 30 years is the age. alter which the overall incidence of cancer increases exponentially (Rubin et al., 1996); the corresponding age in tree shrews would appear to be about 2 years. Most tree shrew neoplasms (n= 22) affected the genital system; 15 testicular tumours in 376 sexually mature (>4 months old) males represented an incidence of 4%. In non-human primates, only approximately 23 such cases have been reported worldwide (Voronofl, 1949; Maruffo, 1967; Palotay and McNulty, 1972; Fiske et al., 1973; Jones et al., 1980; McClure, 1980; Young, 1980; Nogge, 1981, 1993; Minoia and Bufo, 1982; Murphy, 1984; Wadsworth et al., 1985; Hayes and Sass, 1987; Miller and Boever, 1987; Gozalo et al., 1992; Watkins and Warren, 1992). The incidence of testicular tumours in man is rising in industrialized countries (Schnaidt el al., 1992), with germ cell tumours predominating. In the tree shrews, most testicular tumours were of Leydig cell origin. As in man (Hedinger, 1991), such tumours were usually unilateral. In the tree shrews, they were most often found in the left testis. A single hamartoma of the adrcnal cortical tissue type, although not a true tumour, has been included here, because in man the adrenal type dystopias may progress to cortisol-producing tumours (Blumberg-Tick et al., 1991), which sometimes respond to corticosteroid treatment (Rudgers et al., 1988). Intratesticular presence (dystopia) of corticoadrenal tissue, due to early embryonic development of the adrenal primordium and primitive gonads in the adrenal groove ventral to the mesonephros, is not uncommon in man. Intraductal m a m m a r y carcinomas have been described previously in two tree shrews (Elliot el al., 1966; Effron et al., 1977). Four of the five m a m m a r y carcinomas reported here werc either "primary multiple" or had metastasized;

314

M. Brack

the fifth was classified as a "carcinoma in situ", as reported in women (Millis, 1996). All m a m m a r y carcinomas in the present series affected animals between 4"5 and 6"5 years old, i.e., animals still of reproductive age. The malignant lymphomas in 18 animals (1 "6% of all tree shrews examined) usually corresponded histologically to the high grade centroblastic type of the Kiel classification (Lennert, 1981), but immunohistochemical differentiation of T and B cells was beyond the scope of the study. These lymphomas had a remarkable tendency to spread from the site of origin, which was commonly the gastrointestinal or renal lymphoid tissue. The mitotic activity seemed to be high, but could not always be assessed due to post-mortem changes. Pulmonary tumours, which accounted for approximately 20% of all neoplasms in the present series, have not been reported previously in tree shrews. The incidence of 1"5% of all tree shrews examined exceeds the incidences reported in non-human primates (Lombard and Witte, 1957; Jungherr, 1963; Maruffo, 1967; Chesney, 1972; Seibold and Wolf, 1973; McClure, 1980). The occurrence of lung tumours in the tree shrews at the GPC was not related to exposure to tobacco or asbestos, but dust exposure and exposure to radioactivity following the Chernobyl accident have occurred in the past, despite the containment of the animals behind a barrier system. The sex distribution of these tumours (male:female=6:l) in the tree shrews was similar to that (3:1 to 10:1) observed in man (MUller, 1983). Most pulmonary tumours in the tree shrews were papillary adenocarcinomas of bronchial or bronchiolar origin, with a tendency to spread into adjacent alveolar spaces. Histologically, the two recto-anal papillomas, originating at the mucocutaneous junction, resembled the rare polypoid benign squamous cell tumours of the anal canal in man. In one case (4084), the basal cells of the papillomatous rete pegs formed tumour-like, long rows or trabeculae, but changes suggestive of verrucous carcinoma were not observed in either of the cases. The one urinary bladder tumour, which belonged to the highly malignant variety, was associated with a heavy inflammatory response, as in man. Bladder cancer has not been described previously in tree shrews, and only rarely in non-human primates (Chesney, 1972; Chesney and Allen, 1973; Lowenstine, 1986). References

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I Received,June3Oth, 1997 ] Accepted, February l Oth, 1998