L. P. DEHNER,
H. J. NORRIS, Armed Forces Imtitute
F. M. GARNER of Pathology,
and H. B. TAYLOR D.C.
Germ cell tumours represent approximately 25 per cent. of primary ovarian tumours in women (Kent and McKay, 1960), but little is known of their incidence in many other mammalian species. Existing classifications of germ cell tumours are based almost entirely upon studies from women, and little consideration has been given to possible species variations or similarities. This communication describes a group of germ cell tumours of the ovary found in canine, bovine, feline and rodent species. The clinical and pathological features of ovarian germ cell tumours from these species are compared with those from women and reports of other mammals in an effort to explore relationships and standardize the classification of these neoplasms.
Twenty-one germ cell tumours of the ovary have been contributed to the Registry of Veterinary and Comparative Pathology, Armed Forces Institute of Pathology (AFIP) from civilian sources. These occurred in four mammalian species (canine, bovine, feline and rodent). The tumours were classified on the basis of cytological features and histological similarities to comparable tumours in the ovary of man or other animals. In our files, 17 per cent. of canine tumours, 15 per cent. of feline, 8 per cent. of bovine and 20 per cent. of rodent ovarian neoplasms are of germ cell type. RESULTS
The 21 germ cell tumours included 14 dysgerminomas and 7 teratomas, of which 4 were cystic and 3 were solid. The clinical and pathological features of these tumours are summarized in Tables 1 and 2. The pattern of development of mammalian germ cell turnours is shown in Fig. 1. * The opinions or assertions contained construed as official or as reflecting of Defense.
herein are the private views the views of the Department
of the authors and are not to be of the Army or the Department
Canine (white wire-haired terrier) Canine (toy fox terrier)
Bloody vaginal discharge; abdominal mass Bloody vaginal discharge; abdominal mass Bloody vaginal discharge Abdominal mass
Canine (fox terrier) Canine (Boston terrier) Canine (Scottish terrier)
14 13 12
Canine (Scottish terrier)
Canine (cocker spaniel)
Bloody vaginal discharge; abdominal mass
Canine (cocker spaniel)
Feline (Siamese cat)
Feline (domestic cat) Rodent (Springhaus)
Masculine behavior and abdominal mass .. .. .. .
Canine (West Highland terrier)
Canine (Irish terrier)
Size and gross features 13 cm. Nodular mottled reddishwhite surface adherent to omentum 30 cm. Nodular surface with focal haemorrhage 4.5 cm. Firm, tan lobulated surface
2 cm. White and crumbly
4 cm. Fleshy, solid surface 12.5 cm. Tan, solid surface 4 cm. Nodular, solid, fleshy surface Fleshy, lobulated surface
6.5 cm. with smooth external surface. Firm, tan-coloured, lobulated surface 13 cm. Smooth, multilobular external surface. Solid tumour with central haemorrhage and necrosis 20 cm. Thickened white cortical surface 4 cm. Mass weighing 1,000 g. 2 cm. Nodular external surface and homogeneous tan-coloured surface
None None Liver, kidney, mesenteric and mediastinal lymph nodes None
Peritoneum, adrenal Omentum None None
Dysgerminomas Dysgerminomas were identified in 11 dogs covering 4 breeds : terrier (55 per cent.), cocker spaniel (18 per cent.), Scottish terrier (18 per cent.) and collie (9 per cent.). The animals were all purebreds and the median age was 13 years. A pure dysgerminoma was found in a 7-year-old Siamese cat and a mixed dysgerminoma-teratoma occurred in a 6-year-old domestic cat. In addition, a
\I’eight loss ; abdominal mass
Feline (domestic short-haired cat)
Intermittent intestinal obstruction; abdominal mass Sudden death
Sudden death; haemoperitoneum
Size and gross features
12 cm. Cystic with hair, sebaceous material, and bone 3 cm. Solid tumour with bone and hair
1.5 cm. Cystic, haemorrhagic tumour Solid tumour 20 cm., 5.7 kg. Multilocular cysts, widespread calcification 30 cm., 13 kg.
6 cm. Multilocular cysts, focal calcification
Kidneys, uterus, and abdominal lymph nodes None
dysgerminoma was discovered in a Springhaus, a ground squirrel belonging to the rodent species. Signs, when noted, had been present from 1 to 8 months. Fever and lethargy were frequent, occurring in four dogs. A palpable abdominal mass was common (64 per cent.). An associated sanguino-punrlent vaginal discharge was present in four dogs. Masculine behaviour in one Siamese cat suggested aberrant endocrine dysfunction. All the tumours were unilateral, with no predilection for either side. The dysgerminomas ranged in size from 2 to 30 cm., with a mean of 9.5 cm. The mixed dysgerminoma and teratoma of the cat weighed 1 kg. Grossly, the dysgerminomas were nodular masses with slightly bulging, tan-coloured cut surfaces. Variable amounts of haemorrhage and necrosis were commonly observed. Three of the fourteen tumours (21 per cent.) had extended beyond the ovary. Metastatic foci were present in abdominal and mesenteric lymph nodes and the liver as well as in the omentum in two animals, in the liver and kidney in one, and in the adrenals in another. Microscopically, the dysgerminomas were composed of sheets of large polyhedral cells (Fig. 2) septate by strands of connective tissue of varying thickness in a few examples. A separate arrangement characteristic of dysgerminomas in women was seen only in the tumour from the Springhaus (Fig. 3). Nuclei were large and centrally located, and had a prominent chromatin network and nucleolus. The cytoplasm was amphophilic in most instances, but occasionally was vesicular or clear. Mitotic figures were common. Microscopic areas of haemorrhage and necrosis, particularly toward the centre of the tumour, were also frequent. A lymphocytic or granulomatous stromal reaction was rare, in contrast to dysgerminomas in women.
Trophoblastic Differentiation I
Somatic Differentiation 3
of germ cell tumour development in mammalian ovaries to illustrate the concept of origin from primordial germ cells. Dysgerminoma is the least developed pattern, whereas histogenetic differentiation through embryonal carcinoma (right-hand side) to either trophoblastic or somatic structures is shown.
The uterus was enlarged in five dogs. Slides were available in two cases and showed cystic hyperplasia of the endometrium (Fig. 4), suggesting an endocrine disturbance, although this change is a frequent finding in older bitches (Dow, 1959) and may not be related to the dysgerminoma. Four dogs had another neoplasm : a papillary cystadenoma of the opposite ovary; multiple leiomyomas of the uterus; a primary mammary adenocarcinoma without evidence of metastasis; and an adrenal adenoma. Teratomas
Three of the seven teratomas occurred in cattle : two Hereford and one Jersey (Table 2). The other teratomas were found in two dogs, one cat and one California ground squirrel. The initial manifestation in two animals, a cow and a domestic cat, was sudden death resulting from rupture of the tumour or of adjacent ovarian blood vessels. The teratomas in two cows were discovered at the time of slaughter. One dog was presented with emaciation and an abdominal mass containing focal calcification detected radiographically. The other dog had intermittent episodes of intestinal obstruction; a calcified abdominal mass was also identified radiographically. Teratomas were identified in younger animals
(2 to 8 years) than were dysgerminomas. Interestingly, the youngest animal in the group with dysgerminoma was a 6-year-old cat (Case 13, Table 1) with a mixed dysgerminoma and teratoma (Fig. 5). The teratomas were large, especially in cattle. One tumour was described only as “large”, but the other two weighed 5.7 and 13 kg., respectively. Four teratomas were cystic and three were solid. Sebaceous material, hair and calcification were grossly recognizable in three turnours (Fig. 6). Multiple elements were found in these tumours and were fully differentiated adult tissues in most instances. Skin, adnexal structures, neuroglia, fat, muscle and cartilage were prominent (Figs. 7 and 8). Immature elements including foetal mesenchyme, neurectodermal tubes, nests of small, deeply staining undifferentiated cells, and large areas of necrosis were noted in two bovine teratomas (Fig. 9). In one of these two, the tumour had spread beyond the ovary and involved abdominal lymph nodes, kidneys and uterus. The metastases were voluminous and replaced normal parenchyma. Microscopically, neoplastic elements in the metastases were similar to elements in the primary tumour. DISCUSSION
From these observations and those of other workers it is apparent that ovarian germ cell tumours occur in a variety of mammalian species. At least 23 dysgerminomas have been described (Ball and Pommier, 19829; Chabasse, 1954; Cotchin, 1961; McEntee and Zeep, 1953 ; Taylor and Dorn, 1967 ; Gilmore, 1965; Mulligan, 1962; Beurgelt, 1968; Lombard and Havet, 1962); and where incidence figures have been given, they represent 6 to 12 per cent. of ovarian tumours in dogs. Data on cows are lacking and there is not enough known about cats. Aside from the somewhat variable stromal reaction and connective tissue framework prominent in dysgerminomas from women, there is a striking similarity of these tumours in different species. All tumours were composed of a monophasic population of large cells with prominent hyperchromatic nuclei and clear or granular cytoplasm. Dysgerminomas, regardless of species, are malignant, but tend to remain localized to the ovary, where they may attain great size. Asadourian and Taylor (1969) reported that only 16 per cent. of dysgerminomas in women extended or metastasized beyond the ovary at the time of discovery, a finding which compares with spread beyond the ovary in 3 of the 14 dysgerminomas in this study. Additional biological similarities are suggested by a comparison of hormonal activity of dysgerminomas. Approximately 2 per cent. of human dysgerminomas apparently secrete chorionic gonadotropin. Hormone production is also suggested in other mammals (Cases 2,4 and 12, Table 1) by the oestrus-like behaviour (Case 12) and a markedly cystic endometrium (Cases 2 and 4). One curious difference between dysgerminomas of women and those in other species is the age at diagnosis. The tumours in women are almost always found in the first three decades of life (Asadourian and Taylor, 1969). In contrast, the median age in our series was 13 years in dogs and only slightly younger in cats. Dysgerminomas (and seminomas) are neoplasms of primordial germ cells. Unlike other germ cell turnours, they fail to undergo histogenetic differentiation. They are identified on the basis of the cytologic resemblance of tumour cells to
primordial germ cells of the embryo, where they have been described in most mammalian species, including the mouse (Chiquoine, 1954), cat (Vanneman, 1917) and man (Witschi, 1948). A schematic representation of the pattern of development of all mammalian germ cell tumours from a primordial germ cell is shown in Fig. 1. Such a scheme is difficult to support from static observations of a single species, but by using the information from neoplasms from multiple species and identifying a biological model for germ cell tumour development, considerable support for the origin and differentiation of all known germ cell tumors from primordial germ cells is provided. Neoplastic germ cells may pass through successive levels of histogenetic differentiation or may become arrested at any point (Fig. 1). Stevens (1960, 1962, 1967, 1968) demonstrated sequential stages of differentiation from primordial germ cells to mature differentiated tissues in spontaneous testicular teratomas of mice. These tumours arose in the seminiferous tubules of 15-day embryos from cells identified as primordial germ cells. During foetal and infantile development, the tumours have the morphological features of embryonal carcinoma. As the mouse matures, the tumour cells gradually differentiate into a mature adult teratoma. In subhuman mammals there is little or no tendency for differentiation to become arrested in the embryonal stage, and there are no documented examples of embryonal carcinomas in animals. Although embryonal carcinomas of the human ovary are uncommon they do occur in girls and young women and are highly malignant (Neubecker and Breen, 1962). Trophoblastic differentiation of germ cell tumours to form choriocarcinoma rarely, if ever, occurs in animals. The explanation for the absence of trophoblastic differentiation (choriocarcinoma) in non-human species can be explained in part by the non-invasive behaviour of normal trophoblastic tissue in some species, especially marsupials, ungulates and ruminants (Amoroso, 1958). This explanation is not applicable to carnivores, higher rodents and primates, as their trophoblast is able to invade the maternal endometrium. It is likely, therefore, that trophoblastic tumours will be found when enough examples have been studied. Their extreme rarity as primary neoplasms in human gonads suggests that they will also have to be studied to appreciate the full scale of the histological patterns. Teratomas reflect somatic tissue differentiation. Conceptually, these tumours may progress through various stages of maturation, as illustrated on the right side of Fig. 1. Immature (partially differentiated) and mature (fully differentiated) teratomas have been described in a number of mammalian species including canine (Oakley, 1947 ; Benesch, 1935 ; Storm, 1947 ; Riser, Marcus, Guibor and Oldt, 1959) ; feline (Norris, Garner and Taylor, 1969) ; bovine (Plummer, 1956; McEntee and Zeep, 1953 ; Polding and Lall, 1945) ; equine (Norris, Taylor and Garner, 1968 ; Hovel1 and Hignett, 1968) ; murine (Slye, Holmes and Wells, 1920; Jackson and Brues, 1941; Fawcett, 1950; Fekete and Ferrigno, 1952; Thiery, 1963 ; Carter, 1968); rodents other than murine (Schardein, Fitzgerald and Kaump, 1968 ; Flux, 1965 ; Willis, 1962); porcine (Dobberstein, 1953) ; and simian (Crews, Kerber and Feinman, 1967). Incidence figures range from 7 per cent. in the COWS to 15 per cent. in some rodents. On the other hand, only 2 teratomas were found in a survey of 2,000 murine ovarian tumours by Thiery
(1963). The types of tissue found in mature teratomas are histologically similar regardless of species. Benign cystic teratomas comprise 20 per cent. of ovarian tumours in women, but are relatively less frequent in other species. In contrast, solid teratomas with immature elements, common in other mammals, are quite rare in women (Thurlbeck and Scully, 1960). Intermingling of multiple germ cell patterns as is often found in malignant teratomas of women is very rare in other species. A mixed dysgerminoma-teratoma in a cat is the rare exception. SUMMARY
The clinical and pathological features of 2 1 ovarian germ cell tumours (1-l dysgerminomas and 7 teratomas) from four mammalian species are presented. All the dysgerminomas were composed of a monophasic population of cells with a variable type of stromal response, depending upon the species, and 11 of the l-1 were confined to the ovary. Only one dysgerminoma was associated with teratomatous elements. The teratomas were relatively solid, less cystic than those of women, and mature tissue predominated, although solid teratomas contained immature elements capable of metastasis. There were no examples of embryonal carcinoma or choriocarcinoma such as occur in women. From our observations and those of others, coupled with experimental data, it is concluded that germ cell tumours may be divided on the basis of their potential for differentiation. Those failing to express any potential for differentiation persist essentially unchanged as either dysgerminoma or seminoma. Other germ cell tumours have some potential for tissue differentiation. That potential may lead to a very restricted and immature differentiation, such as embryonal carcinoma or choriocarcinoma as in women. Beyond the primordial germ cell stage, germ cell tumours in other mammals primarily manifest somatic differentiation (teratomas). Among the tumours exhibiting differentiation, the clinical behaviour tends to parallel the degree of differentiation. At one end of the germ cell spectrum is the primitive and highly malignant embryonal carcinoma, and at the other is the benign adult cystic teratoma. REFERENCES
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Endometrial h yperplasia in a 14-year-old toy fox terrier with an enlarged uterus and a dysgerminoma. x 55. Mixed dysg~rminoma-teratoma in a cat. The tumour is composed of neoplastic primordial germ cells (insert) admixed with mature teratomatous elements including glands and adipose tissue. >: 80. Insert: :- 240.
.\ solid .< 0.65. Ncuroglia cat.
in the ovarv
and a nest of squamous 55.
of a :i-)car-old epithrlium
in a trratoma