Clinicopathological Evidence of Pseudomyxoma Peritonei in a Dog With Intestinal Mucinous Adenocarcinoma

Introduction

Pseudomyxoma peritonei (PMP) is an uncommon and poorly understood disorder of humans characterized by deposition of mucinous pools in serosal surfaces and accumulation of mucinous/gelatinous material (i.e., gelatinous ascites) within the peritoneal cavity.^1–3 Pseudomyxoma peritonei was first described in 1884 by Werth in association with a mucinous tumor of the ovary.⁴ In humans, PMP is usually associated with benign or malignant tumors of the appendix or ovary.^1–3

This report describes a case of canine PMP associated with a mucinous adenocarcinoma of the jejunum. The diagnosis of PMP was supported by gross and cytopathological evaluations of the peritoneal effusion and was confirmed by histopathology.

Case Report

An 11-year-old, intact female Pekingese dog was presented with a 1-month history of weight loss and recurrent vomiting. On clinical presentation, the dog appeared thin with a body condition score of 2 (range, 1 [emaciated] to 5 [obese]).⁵ On general physical examination, findings included the presence of two, firm, inguinal, 1 × 1.5-cm symmetrical nodules; a systolic (III/VI) heart murmur; and a 3- to 4-cm, firm, midabdominal mass on palpation. The latter was suspected to be of intestinal or mesenteric lymph-node origin. Thoracic and abdominal radiographs demonstrated slight cardiomegaly, a diffuse reduction in the abdominal radiographic detail, and a poorly demarcated, 3 × 4-cm oval mass in the midabdomen. Ultrasonography confirmed the presence of a hyperechoic, oval, well-demarcated mass associated with the small intestine. An ultrasound-guided, fine-needle aspiration biopsy yielded fecal material and was considered nondiagnostic. The abdominal mass was presumed to be a distended segment of bowel containing a hard fecal mass. The inguinal nodules were interpreted as bilateral inguinal hernias. A fine-needle aspirate was performed on these hernias and yielded dense, gelatinous material grossly that on cytopathological evaluation revealed moderate numbers of macrophages and spindle cells that were embedded in abundant, bluish, amorphous material (i.e., mucin). The owner declined laparotomy and further investigations at this stage.

Two months later, the dog was represented because of daily vomiting. The body condition score was 1, and the dog appeared depressed, was mildly dehydrated, and was also hypothermic (rectal temperature, 37.5°C). On general physical examination, the abdomen appeared slightly distended and tender, and the inguinal and abdominal masses had a similar size and consistency as before. A complete blood count (CBC), serum biochemistry profile, and urinalysis were performed. The CBC revealed a mild normochromic, normocytic, nonregenerative anemia (packed cell volume, 30%; reference range, 37% to 55%); a mild, mature neutrophilia (segmented neutrophils, 14.4 × 10³/μL; reference range, 3.0 to 11.5 × 10³/μL); and lymphopenia (lymphocytes, 620/μL; reference range, 1.0 to 4.8 × 10³/μL). On serum biochemistry analysis, abnormalities included hypoalbuminemia (albumin, 1.5 g/dL; reference range, 2.5 to 4.0 g/dL) and elevations in alanine aminotransferase (ALT, 409 UI/L; reference range, 10 to 46 UI/L) and aspartate aminotransferase (AST, 101 UI/L; reference range, 10 to 30 UI/L) activities. Due to the persistent and progressive clinical findings, the owners elected an exploratory celiotomy.

Intravenous (IV) fluid therapy was started with lactated Ringer’s solution (10 mL/kg body weight per hour for 4 hours and a maintenance rate thereafter). The dog was pre-medicated with atropine sulfate (0.02 mg/kg body weight, intramuscularly), was induced with diazepam (0.4 mg/kg body weight, IV) and ketamine (5 mg/kg body weight, IV), intubated, and maintained on halothane in oxygen. Cefazolin (20 mg/kg body weight, IV) was also administered perioperatively. The celiotomy revealed the accumulation of a gelatinous/mucinous, clear, slightly turbid fluid in the peritoneal cavity [Figure 1]. Cytopathological evaluation of this fluid revealed macrophages, spindle cells, and reactive mesothelial cells embedded in an abundant, amorphous, basophilic material [Figure 2A]. Occasionally, condensed filaments of mucin resembling Curschmann’s spirals were present [Figure 2B]. The previously palpable mass was found to be a 6-cm long, annular, diffuse thickening of the intestinal wall of the midjejunum. This segment was also distended and contained a firm, 4-cm, round, dry, fecal accumulation containing hair. Subperitoneal gelatinous material had accumulated in the serosal surface of the abdominal organs (i.e., liver, spleen, stomach, small and large bowel, diaphragm, mesentery, and pancreas) and in the parietal peritoneum. The mesentery, small and large omentum, and mesometrium appeared tense, fibrotic, and retracted. Mucometra was an additional finding. Enterectomy and ovariohysterectomy were performed, and biopsy samples from mesenteric fat were taken. Twenty-four hours after recovery from anesthesia, a cardiopulmonary arrest occurred. Despite cardiopulmonary resuscitation, the dog died 2 hours later.

A necropsy was performed and correlated with the gross findings at celiotomy. Samples of multiple organs were taken and fixed in 10% buffered formalin and submitted for histopathology.

On histopathology, the lamina propria and the muscularis mucosae of the thickened portion of the jejunum were completely effaced and severely expanded by neoplastic epithelial cells arranged in tubules, nests, or irregular cords. Neoplastic cells extended to the muscular layers and multifocally invaded the peritoneum and the mesentery. The epithelial nests were surrounded by mucin and moderate to severe desmoplasia [Figure 3A]. The cords and some tubules were composed of cubical to columnar palisading cells characterized by an elevated nuclear to cytoplasmic ratio, a moderate amount of basophilic cytoplasm, and oval to irregular vesicular nuclei with one to three small nucleoli. Mitotic figures were rare, with the exception of the groups of cells organized in cords that demonstrated 0 to 4 mitoses per high-power field. A second pattern of neoplastic growth in the tumor was characterized by cells organized in tubules with a low nuclear to cytoplasmic ratio, moderate and eosinophilic cytoplasm, and marginated, oval to pleomorphic nuclei with condensed chromatin [Figure 3B]. Mitotic figures among this population were extremely rare. The lumen of these tubules contained variable amounts of basophilic to amphophilic material often organized in strands (i.e., mucin) [Figure 3B]. In many areas, the tubular epithelium was degenerate, necrotic, or lost with mucin accumulation in large lacunae (up to 80 μm in diameter) [Figure 3B]. In the peritoneum and in the mesenteric fat, septal fibrosis and elevated amounts of mucin entrapped in a fibrous reticular mesh were present. The peritoneal surface of the diaphragm was characterized by epimysial thickening and diffuse fibrosis with admixed neutrophils and hemorrhages. Thick, fibrous septa, originating from the diaphragmatic surface, surrounded and entrapped a large amount of mucin. Multifocal, floccular, and discoid myocyte degeneration with occasional regenerating multinucleated fibers was also visible. All the histopathological findings were consistent with an infiltrating, intestinal mucinous adenocarcinoma with mesenteric dissemination and mucin accumulation.

Discussion

Primary intestinal neoplasms are uncommon in dogs, representing <1% of all malignancies and with a prevalence of adenocarcinoma.⁶⁷ Mucinous adenocarcinoma can occur in any segment of the intestine, but it has been found more commonly in the jejunum and rectum.⁶⁷ Mucinous intestinal adenocarcinoma can extend transmurally to the mesentery with accumulation of variable amounts of mucin.⁶ Microscopic findings observed in this case closely resembled those involving the jejunum described by Patnaik, et al.⁶ According to these authors, a large accumulation of mucin occurred both in the primary tumor and in abdominal organs; however, no mention of concurrent “gelatinous ascites” was documented.⁶ To the authors’ knowledge, this case represents the first report of PMP in the veterinary literature.

Despite the large series of PMP reported in humans, PMP remains a poorly understood condition, and its pathogenesis continues to generate controversy.³ The finding of gelatinous ascites has been attributed to several mechanisms. One hypothesized mechanism is the spillage of mucin into the abdominal cavity resulting from the rupture of a mucin-producing tumor.¹² However, experimental studies in animals have failed to cause PMP by rupture of artificially induced appendiceal mucoceles, indicating that increased production of mucin in an organ is not sufficient to cause PMP.² In humans, PMP has been described in association with a number of disorders, including benign and malignant mucinous epithelial tumors of the appendix or ovaries,^1–3 pancreatic colloid carcinoma,⁸ fallopian tube low-grade malignancy,⁹ endometriosis,¹⁰ metastatic breast colloid carcinoma,¹¹ omental teratoma,¹² and colonic tumors.²¹³ Interestingly, human PMP is more commonly associated with benign tumors. In these cases, peritoneal implantation of benign, mucin-producing epithelium can be found outside the primary tumor secondary to leakage of epithelial cells from an adenoma into the peritoneal cavity.¹ Another mechanism of PMP formation has been evidenced in association with gastrointestinal mucinous adenocarcinoma that may infiltrate the visceral wall or metastasize to the peritoneum, resulting in spillage of mucin in the abdominal cavity and disseminated mucin production.² In the case of this report, PMP was associated with the diagnosis of an invasive intestinal adenocarcinoma. Histopathological evidence of transmural invasion of the intestinal wall and peritoneal spreading of neoplastic malignant cells were detected. These findings supported the hypothesis of PMP formation by mucin spillage and continuous mucin production by neoplastic cells implanted in mesenteric fat and peritoneum.

Cytopathological features observed in the case of this report closely resembled those of PMP described in humans.¹⁴ Accurate cytopathological evaluation of the mucinous effusion in human cases of PMP appears to bear prognostic significance. Absence of neoplastic cells in the mucin deposits correlates with improved survival in humans, while PMP-containing neoplastic epithelial cells (so-called “cellular PMP”) have been associated with a shorter survival time.¹⁴ In the case of this report, the mucinous tumor was an infiltrating adenocarcinoma of the jejunum, but the authors failed to find any evidence of cellular PMP in the cytopathological preparations of the abdominal fluid. However, histopathology clearly demonstrated the dissemination of neoplastic mucin-producing cells outside the primary tumor. These discordant findings might be explained by an insufficient cytopathological serial sampling. This is supported by the recommendation to evaluate large amounts of gelatinous effusion in humans if the cytopathological findings are to be considered significant.¹²¹⁴

Appropriate therapy for PMP in humans is difficult to determine.¹ Surgical resection of gross disease and peritonectomy have been suggested to maximally cytoreduce the tumor.¹² Resection of primary nonmalignant tumor can resolve all clinical signs, whereas patients who harbor adenocarcinoma have a much worse prognosis.¹² The role of adjuvant therapies such as systemic or intracavitary chemotherapy and radiation therapy is less clear.¹²

In humans, accumulation of gelatinous fluid inside inguinal hernia sacs has been reported in association with mucinous appendiceal tumors.¹⁵ The presence of mucinous material inside both inguinal canals in this case report is theorized to be the result of the gravitational forces causing the gelatinous fluid to settle in the lower portion of the abdominal cavity.²

Conclusion

To the authors’ knowledge, this is the first case report of “gelatinous ascites” associated with a mucin-producing jejunal adenocarcinoma in a dog. The authors suggest including “gelatinous ascites” in the differential diagnosis of canine peritoneal effusions.