History
A 5-year-old male castrated medium-sized long-haired crossbreed dog was transferred to the University College Dublin Veterinary Hospital for further investigation of weight loss, melena, decreased appetite, lethargy, and infrequent vomiting over a 9-month period.
Clinical and Gross Findings
On physical examination, the dog was bright and alert with poor body condition (2/9) and generalized, severe muscle atrophy. Hematology revealed a mild, macrocytic, normochromic, regenerative anemia and mild leukocytosis. Serum biochemistry was unremarkable other than hypoproteinemia (total protein, 40.8 g/L [reference range, 54 to 71 g/L]; albumin, 24.3 g/L [reference range, 25 to 38 g/L]; and globulin, 16.5 g/L [reference range, 28 to 42 g/L]). Abdominal ultrasonography revealed that the entire duodenum and most of the jejunum were markedly thickened (up to 1.46 cm). Endoscopic examination showed widespread dense, small, irregular mucosal nodular thickenings in the stomach and duodenum (Figure 1). Results from multiple superficial gastric and duodenal endoscopic biopsies were most consistent with marked lymphoplasmacytic and neutrophilic enteritis. Both T and B cell markers tested by Laboklin (Laboratory for Clinical Diagnostics; GmbH & Co KG) with PCR for antigen receptor rearrangement were polyclonal. This result confirmed that lymphoid cells in the intestine were inflammatory rather than neoplastic.
Endoscopic (A) and postmortem images (B and C) of the gastrointestinal tract of a 5-year-old crossbreed dog. A—Numerous masses arising from the duodenal mucosa are obliterating the lumen. B and C— Innumerable variably sized polyps cover the mucosa of the entire duodenum and jejunum, causing marked mucosal thickening and obstruction of the intestinal lumen.
Citation: Journal of the American Veterinary Medical Association 261, 2; 10.2460/javma.22.08.0356
Treatment with novel protein diet, prednisolone, amoxycillin clavulanate, metronidazole, cyanocobalamin, and omeprazole caused a noticeable improvement in appetite, but intermittent diarrhea and low body condition persisted. Further investigations were declined, and the dog was euthanized 2 months later.
Postmortem examination confirmed a very poor body condition with serous atrophy of cardiac fat and marked dehydration. In the duodenum and jejunum, 70% to 80% of the mucosa was covered by innumerable multifocal to coalescing firm polypoid masses of varying size (0.3 cm to 6.5 cm in diameter) and shape (buttoned, pedunculated, or cauliflower-like) that partly obliterated the lumen (Figure 1). A few nodular raised masses of smaller size (0.1 to 0.3 cm in diameter) were also noted in the gastric mucosa. Innumerable small (up to 0.5 cm in diameter), white firm nodules were present in the gingiva, dermis, and subcutis and on the visceral serosal surfaces, especially on the mesentery and intestinal serosa. Multiple cysts of up to 3 cm in diameter were observed in the thyroid, liver, bile duct, prostate, and kidneys.
Histopathologic Findings
The histopathologic examination of the duodenum and jejunum revealed multifocal to coalescing mucosal polyps supported by thin fibrovascular tissue (Figure 2). These were lined by a single layer of high columnar cells with basally located oval nuclei with fine stippled chromatin interspersed with frequent goblet cells. Larger masses branched into tubules and papillae, with frequent foci of necrosis and rare foci of carcinoma in situ, characterized by multiple layers of large cuboidal cells with central large vesicular nuclei. The mitotic count was high, with up to 12 mitotic figures/hpf (0.273 mm2). Numerous crypts were severely dilated, and some of these showed abundant neutrophilic infiltrates admixed with mucous and eosinophilic cell debris (crypt abscesses). The lamina propria was densely infiltrated by plasma cells, lymphocytes, and few neutrophils. The small, firm, white, well-demarcated nodules in the gingiva, subcutis, and serosae were composed of haphazardly arranged, thick collagen bundles and thin, elongated fibroblasts. Microscopic examination of the kidneys and prostate showed multifocal to coalescing cysts lined by a single layer of cuboidal cells. Papillary projections with thin fibrovascular tissue stalks were also lined by these cuboidal cells (cystadenomas). Multifocal cysts lined by attenuated epithelium were present in thyroid gland, liver, and bile duct.
Photomicrographs of tissue sections from small intestine. A—Adenomatous polyps are composed of branching tubules, that are multifocally dilated by bright eosinophilic fluid and mucin and papillae with fine fibrovascular tissue stalks. H&E stain; bar = 750 µm; 125X magnification. B—A florid inflammation is infiltrating the lamina propria. The black arrow is indicating a focus of carcinoma in situ characterized by multiple layers of large cuboidal cells with central large vesicular nuclei. H&E stain; bar = 50 µm; 200 X magnification.
Citation: Journal of the American Veterinary Medical Association 261, 2; 10.2460/javma.22.08.0356
Morphologic Diagnosis and Case Summary
Morphologic diagnosis: adenomatous polyposis of stomach and small intestine associated to dermal and visceral dermatofibrosis, renal and prostate cystadenomas, and thyroid, hepatic, and biliary cysts.
Case summary: protein-losing enteropathy (PLE) caused by gastric and small intestinal adenomatous polyposis.
Comments
Adenomatous polyposis, characterized by hundreds to thousands of polyps arising from the gastrointestinal mucosa, has rarely been reported in dogs.1,2 By contrast, familial adenomatous polyposis represents a well-known cancer syndrome in humans associated with autosomal dominant mutations in APC, a tumor-suppressor gene.3 Loss of the APC gene leads to accumulation of β-catenin in the nucleus, followed by activation of the Wnt signaling pathway, which is the dominant mitogen for crypt progenitor cells.3 Adenomatous polyposis, with an underlying mutation on the APC gene, has been recently reported in Jack Russell Terriers in Japan.2 Another single case of polyposis restricted to the small intestine was reported by Wang et al1 in a dog carrying a conserved APC gene. The presentation of the dog examined here differs from the previous reports of canine adenomatous polyposis since the manifestation was associated with several primary neoplasms in different tissues, such as prostatic and renal cystadenomas and nodular fibromatosis of skin and viscera (Figure 3). In addition, immunohistochemistry using an antibody against β-catenin (clone 14, Ventana 760-4242; F Hoffmann-La Roche Ltd) on the intestinal polyps showed a cytoplasmatic distribution of the protein in the absence of nuclear labeling similar to what was observed in control intestinal tissues from an unaffected dog. This result suggests that the APC gene was conserved in this case; however, APC gene sequencing would be required to confirm this.
Postmortem images of the kidney (A) and skin (B) of a 5-year-old crossbreed dog. A—Renal cystadenomas in the kidney of a dog. Multifocal cysts are seen within the renal cortex, with some surrounded by a white, firm rim. The cystic structures were evident at ultrasound but were not of clinical relevance. B—Multifocal to coalescing, innumerable small, white, firm nodules are present in the subcutis. The nodules were not palpable on intact skin.
Citation: Journal of the American Veterinary Medical Association 261, 2; 10.2460/javma.22.08.0356
Polyps in the small and large intestines have also been linked to a dominant, hereditary cancer syndrome called renal cystadenocarcinomas and nodular dermatofibrosis (RCDN) in German Shepherd Dogs and rarely in other breeds.4 Nodular dermatofibrosis is characterized by multiple cutaneous or subcutaneous nodules of dense collagen tissue and manifests in association to renal cystadenomas, cysts, and cystadenomas in other organs, as seen in this case. A missense mutation in the exon 7 of the folliculin gene (FLCN), the role of which in the disease remains unclear, has been linked to RCDN manifestation.4 Despite the similarities, results from Sanger sequencing of the folliculin exon 7 in this case indicated that this dog did not have this specific mutation. Due to the lack of information and samples from any siblings or parents of the dog, further genetic investigations were not performed.
Of all the pathologies found in this dog, only the adenomatous polyposis was of clinical significance, causing a severe form of PLE and subsequent emaciation. Protein-energy malnutrition in severe and prolonged forms results in depletion of fat seen as serous atrophy; gelatinous, clear pink material in bone marrow, in the coronary groove, and around the kidneys; and reduction in muscle mass.5 Protein loss through the intestinal mucosa is considered nonspecific, hence the panhypoproteinemia in these cases. Abnormal permeability of intact mucosa, mucosal ulcerations or erosions leading to secondary protein exudation, and lymphatic disruption with leakage of protein-rich lymph are the leading causes of PLE.5 Mucosal ulceration associated to epithelial necrosis, increased enterocyte exfoliation, blockage of the lymphatic flow with lacteal dilation, and inflammatory infiltrates of the lamina propria were evident at histopathology in this case, which would have resulted in the severe PLE. Intestinal lymphoma and granulomatous enteritis are other common causes of PLE that, like adenomatous polyposis, manifest with formation of intestinal masses and should be differentiated through histological examination.
Through this case report, we showed that adenomatous polyposis should be considered as a differential diagnosis for protein-losing enteropathy in dogs. We would further like to highlight that, to reach the histopathology diagnosis, deeper sampling through endoscopic polypectomy or full-thickness biopsy may be necessary to confirm the diagnosis as only superficial fragments of the polyps may be misinterpreted for an inflammatory process. Given the high number of polyps and concomitant multiple primary tumors in a young adult dog, an underlying oncogene germline mutation is likely but could not be linked to APC mutation or RCDN by preliminary investigation. Whole genome sequencing of this case and future cases would help identify the genetic mutations.
Acknowledgments
The authors wish to thank Mr. Brian Cloak, University College Dublin, School of Veterinary Medicine, for taking the macroscopic images. Technical assistance was given by Susan Peters and Erin Markle, University College Dublin, School of Veterinary Medicine, and Robert Geraghty, University College Dublin, School of Medicine.
References
- 1.↑
Wang J, Wang T, Bishop MA, et al. Collaborating genomic, transcriptomic and microbiomic alterations lead to canine extreme intestinal polyposis. Oncotarget. 2018;9(49):29162–29179. doi:10.18632/oncotarget.25646
- 2.↑
Yoshizaki K, Hirata A, Nishii N, et al. Familial adenomatous polyposis in dogs: hereditary gastrointestinal polyposis in Jack Russell Terriers with germline APC mutations. Carcinogenesis. 2021;42(1):70–79.
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Half E, Bercovich D, Rozen P. Familial adenomatous polyposis. Orphanet J Rare Dis. 2009;4:22. doi:10.1186/1750-1172-4-22
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Lingaas F, Comstock KE, Kirkness EF, et al. A mutation in the canine BHD gene is associated with hereditary multifocal renal cystadenocarcinoma and nodular dermatofibrosis in the German Shepherd Dog. Hum Mol Genet. 2003;12(23):3043–3053.
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Uzal FA, Plattner BL, Hostetter JM. Alimentary system. In: Maxie MG, ed. Jubb, Kennedy & Palmer’s Pathology of Domestic Animals. Vol 2. 6th ed. WB Saunders; 2016:1–257.
