History
A 12-year-old sexually intact female Vietnamese potbellied pig (Sus scrofa) was evaluated at the Auburn University Large Animal Teaching Hospital because it was nonambulatory unless coerced to move. The gilt had a history of chronic pneumonia that was unresponsive to antimicrobial treatment and palliative treatments. It was housed in an outdoor enclosure with a housemate, a 14-year-old sexually intact male Vietnamese potbellied pig, that also had a history of chronic pneumonia. The gilt's diet consisted of a standard ration of commercial mini pig chow, and dietary supplements were not provided. The reproductive history and current estrus status of the gilt were unknown. The gilt's condition had rapidly deteriorated during the preceding week, and the client requested euthanasia upon initial evaluation. Antemortem diagnostic procedures, including CBC, serum biochemical analysis, urinalysis, and radiography, were not performed.
Gross Findings
A complete necropsy of the gilt revealed that the right ovary was entirely replaced by an 8.7-cm-diameter, multinodular, firm, white mass containing dense intervening bands of connective tissue (Figure 1). The contralateral ovary was atrophic with scattered follicles ranging from 2.0 to 4.0 mm in diameter, and there was no evidence of a corpus albicans or corpus luteum. The uterus was diffusely enlarged (approx 3 times the dimensions expected for the uterus in a healthy Vietnamese potbellied pig) and was filled with opaque, gray-green, malodorous fluid. The endometrium was thickened by variably sized, 1.0-mm- to 1.5-cm-diameter, thin-walled, fluid-filled cystic spaces. Ten to fifteen 1.0- to 3.0-cm-long, zonal to segmental, transmural regions of the endometrium and underlying myometrium were expanded and infiltrated by dense, firm, white, multinodular masses. The luminal surface was friable and would easily break off into the uterine lumen. The cervix was constricted and the vaginal mucus scant.
Photograph of the uterus and right ovary obtained during the necropsy of a Vietnamese potbellied pig (Sus scrofa). The pig had a history of chronic pneumonia. Notice that the ovary is effaced by a firm, white, multinodular mass (asterisk) and zonal regions of the endometrium are expanded by similar firm, white, multinodular masses (arrowheads). The remainder of the endometrium is thickened by fluid-filled cystic spaces.
Citation: Journal of the American Veterinary Medical Association 243, 10; 10.2460/javma.243.10.1403
The lung lobes were mottled pink to red to purple and rubbery to slightly firm. Yellow-tinged serosanguineous fluid and froth filled the mainstem bronchi and lower airways. Several slightly depressed, dark-red areas of atelectasis and intense congestion were interspersed throughout the lung, predominantly in the perihilar regions.
Formulate differential diagnoses from the history, clinical findings, and Figure 1—then turn the page →
Histopathologic Findings
Sections of uterus, ovaries, and lungs were fixed by immersion in neutral-buffered 10% formalin, routinely processed, embedded in paraffin, sectioned at 4 to 6 μm, and stained with H&E stain for microscopic examination. Histologically, there was effacement of the ovarian parenchyma of the right ovary by a poorly delineated, infiltrative, and densely cellular neoplasm (Figure 2). This mass was composed of markedly pleomorphic, nonciliated, polygonal cells arranged in broad sheets and rare, rudimentary tubuloacinar structures supported by a delicate fibrovascular stroma. Individual neoplastic cells ranged from 12 to 25 μm in diameter with a nuclear-to-cytoplasmic ratio of approximately 3.5:1. Cells had a modest rim of homogenous to fine fibrillar to microvacuolated cytoplasm, with most cells having distinct cellular margins. In some areas, the close proximity of the cells precluded observation of the cellular borders. Nuclei were extremely variable, ranging from 10 to 20 μm in diameter, and round to oval to slightly reniform. Occasionally, binucleate cells were evident. The chromatin was dispersed toward the nuclear membrane, and cells frequently had a single, deep magenta, centrally located nucleolus. Fifteen mitotic figures were observed in 10 contiguous 400× fields. Many apoptotic cells, aggregates of cellular debris, and large confluent areas of ischemic necrosis were interspersed among the neoplastic population. Immunohistochemical staining revealed that the neoplastic cells had strong, diffuse cytoplasmic and membrane staining for pancytokeratin but no reaction to anti-human c-KIT antibody (CD117). Scattered intralesional mast cells strongly expressed c-KIT, which served as an internal positive control for c-KIT immunostaining in swine tissues. Histologic abnormalities were not observed in sections of the left ovary.
Photomicrograph of a section of a mass in the uterus (presumed metastasis) of the gilt in Figure 1. A markedly pleomorphic population of neoplastic epithelial cells arranged in sheets and rare tubuloacinar structures (arrowheads) replaces the normal endometrial architecture. Few small bands of uterine smooth muscle tunics remain (asterisk). H&E stain; bar = 100 μm.
Citation: Journal of the American Veterinary Medical Association 243, 10; 10.2460/javma.243.10.1403
Similar to findings in the right ovary, there was zonal effacement of the uterine architecture by broad sheets of neoplastic epithelial cells. In many areas, the neoplastic cells effaced the myometrium and only small bands of uterine smooth muscle tunics remained. Aggregates of small lymphocytes were interspersed among the remaining smooth muscle tunics, often in an angiocentric pattern. The remainder of the uterine endometrium was arranged in variably sized cystic spaces lined by pseudostratified layers of ciliated cuboidal epithelium and containing varying amounts of proteinic fluid and cellular debris (cystic endometrial hyperplasia; Figure 3). The intervening stroma was composed of dense fibrocollagen and myoepithelium containing small-caliber arteries, veins, and lymphatic spaces.
Photomicrograph of a section of affected uterine endometrium obtained from the gilt in Figure 1. Variably sized cystic spaces lined by pseudostratified epithelium comprise the remainder of the uterine endothelium. H&E stain; bar = 1.0 mm.
Citation: Journal of the American Veterinary Medical Association 243, 10; 10.2460/javma.243.10.1403
There was no evidence of pulmonary metastasis, but rather, pulmonary changes were limited to chronic, insidious interstitial pneumonia and alveolar septa were minimally expanded by sparse numbers of lymphocytes and plasma cells. The perihilar alveolar spaces contained extensive edema, and the alveolar capillaries were moderately congested. Ancillary microbial testing (ie, virus isolation, mycoplasmal PCR assay, and routine bacteriologic culture of lung samples) did not reveal the presence of microbial pathogens.
Morphologic Diagnosis and Case Summary
Morphologic diagnosis and case summary: ovarian carcinoma with multifocal uterine metastasis and diffuse cystic endometrial hyperplasia in a Vietnamese potbellied pig.
Comments
In the Vietnamese potbellied pig of this report, the final diagnosis of ovarian carcinoma with uterine metastasis and diffuse cystic endometrial hyperplasia was supported by gross, histologic, and immunohistochemical findings. Differential diagnoses for ovarian tumors in swine should include gonadal stromal tumors (granulosa theca cell tumor, thecoma, and interstitial cell tumors), germ cell tumors (dysgerminoma, teratoma, and embryonal carcinoma), epithelial tumors (papillary adenoma and cystadenoma, rete adenoma, and carcinoma), and mesenchymal tumors (hemangioma and leiomyoma).
In the case described in the present report, the gross and histologic features observed did not support the diagnosis of a gonadal stromal tumor; considering also the pancytokeratin immunoreactivity, tumors of mesenchymal origin were also excluded from the list of differential diagnoses. Typically, germ cell tumors such as dysgerminoma and seminoma are strongly positive for c-KIT (CD117) and have weak or no immunoreactivity for pancytokeratin in humans.1 This immunohistochemical profile contradicts observations in the present case, thereby excluding dysgerminoma from the list of differential diagnoses.
Tumors arising from the ovarian surface epithelium or, rarely, from the epithelium of the rete ovarii are uncommon in all domestic animals, with the notable exception of bitches.2 Epithelial tumors are usually cystic and papillary and filled with yellow or brown fluid. Solid sheets and rare, rudimentary tubuloacinar profiles of neoplastic cells that were strongly immunoreactive for pancytokeratin were indicative of an epithelial cell of origin for the neoplasm in the pig of this report, supporting the diagnosis of ovarian carcinoma. Ovarian carcinomas in other species have a relatively high metastatic potential, including transcoelomic peritoneal implantation.3 Given the size of the ovarian neoplasm and random distribution of uterine lesions, it is plausible that this is a unique case of ovarian carcinoma in a Vietnamese potbellied pig with transcoelomic seeding of the uterine wall. Ovarian tumors in pigs are rarely reported; however, reports of hyperplastic and neoplastic uterine lesions are more frequent, especially in aging pet pig populations.
Ovarian neoplasms, irrespective of type, may stimulate the ovarian stroma with concomitant production of sex hormones. Excessive endometrial estrogen receptor (ER) stimulation associated with repeated estrous cycles has been attributed to the development of cystic endometrial hyperplasia in cattle.4 In a study5 of 32 miniature pigs, cystic endometrial hyperplasia developed alone or in conjunction with uterine smooth muscle tumors or nodular mucosal changes. In addition, cystic endometrial hyperplasia in conjunction with uterine adenocarcinoma in a Vietnamese potbellied pig has been reported.6 Although the cause of hyperestrogenism was not identified in the case study5 of 32 miniature pigs nor in the gilt of the present report, it is plausible that repeated estrous cycles in nulliparous sows may cause excessive endometrial ER stimulation.
Endogenous hormones often play a role in the development of reproductive tumors. The influence of ERs and progesterone receptors (PRs) is well documented in other species, and low expression or absence of expression is correlated with tumor invasiveness and metastatic potential.7–9 However, there are few reports regarding the role of ERs and PRs in the pathogenesis of genital neoplasms in domestic and pet pigs. In the case study5 describing uterine lesions among 32 female miniature pigs, nuclear expression of ERs and PRs was intense and diffuse in smooth muscle and epithelial tumors and regions with benign epithelial hyperplasia. The intensity and distribution of these receptors in sections of these neoplasms and unaffected uterine tissue were similar, which may be a reflection of the benign nature or low metastatic potential of these neoplasms. In a case of metastatic uterine adenocarcinoma in an 8-year-old gilt, neoplastic cells lacked expression of ERαs and PRs.10 These results were consistent with the invasiveness, marked cellular atypia, and metastasis reported for uterine adenocarcinoma in other species.
Inherited genetic predisposition to tumor formation is a feature of hormonal carcinogenesis in humans and may also be important in animals.11 The genetic pool for pet pigs including Vietnamese potbellied pigs in the United States is restricted. An inbred population of Vietnamese potbellied pigs may have provided much of the seeder stock for the pet pig population in the United States, considering that numbers of pet Vietnamese potbellied pigs sharply increased in the mid-1990s. As nulliparous females aged, the initial reports of uterine lesions in these pet pigs surfaced in 2002 to 2004.6,12 Collectively, the case described in this report and the other published reports suggest that aging, nulliparous female swine may be predisposed to ovarian and uterine tumor development and cystic endometrial hyperplasia.
References
1. Ulbright TM, Young RH. Seminoma with tubular, microcystic and related patterns: a study of 28 cases of unusual morphologic variants that often cause confusion with yolk sac tumor. Am J Surg Pathol 2005; 29:500–505.
2. Park JK, Goo MJ, Hong IH, et al. Immunohistochemistry diagnosis of an ovarian dysgerminoma in one bitch. Reprod Domest Anim 2009; 44:855–858.
3. MacLachlan NJ. Ovarian disorders in domestic animals. Environ Health Perspect 1987; 73:27–33.
4. Kimmins S, MacLaren LA. Oestrous cycle and pregnancy effects on the distribution of oestrogen and progesterone receptors in bovine endometrium. Placenta 2001; 22:742–748.
5. Ilha MRS, Newman SJ, van Amstel S, et al. Uterine lesions in 32 female miniature pet pigs. Vet Pathol 2010; 47:1071–1075.
6. Harmon BG, Munday JS, Crane MM. Diffuse cystic endometrial hyperplasia and metastatic endometrial adenocarcinoma in a Vietnamese pot-bellied pig (Sus scrofa). J Vet Diagn Invest 2004; 16:587–589.
7. Flake GP, Andersen J & Dixon D. Etiology and pathogenesis of uterine leiomyomas: a review. Environ Health Perspect 2003; 111:1037–1054.
8. Millán Y, Gordon A, de los Monteros AE, et al. Steroid receptors in canine and human female genital tract tumors with smooth muscle differentiation. J Comp Pathol 2007; 136:197–201.
9. Watanabe K & Suzuki T. Uterine leiomyoma versus leiomyosarcoma: a new attempt at differential diagnosis based on their cellular characteristics. Histopathology 2006; 48:563–568.
10. Cannon CZ, Godfrey VL, King-Herbert A, et al. Metastatic uterine adenocarcinoma in an 8-year-old gilt. J Am Assoc Lab Anim Sci 2009; 48:795–800.
11. Cullen JM, Page R & Misdorp W. An overview of cancer pathogenesis, diagnosis and management. In: Meuten DJ, ed. Tumors in domestic animals. 4th ed. Ames, Iowa: Iowa State Press, 2002; 3–44.
12. Munday JS, Stedman NL. Uterine leiomyomas in two Vietnamese pot-bellied pigs (Sus scrofa). Vet Pathol 2002; 39:580–583.
