Uterine Disorders in 50 Pet Rabbits

Introduction

According to the literature, uterine disorders in rabbits most often comprise endometrial hyperplasia and uterine adenocarcinoma.^1,2 Sporadically, other neoplastic changes of the uterus such as leiomyoma, leiomyosarcoma, adenoma, carcinosarcoma, choriocarcinoma, malignant mixed müllerian tumor as well as nontumorous uterine lesions (e.g., hydrometra, mucometra, endometritis, pyometra, endometrial venous aneurysms, uterine torsion) have been described in rabbits.^1–7 Uterine disorders commonly occur in middle-aged and older rabbits, but endometrial hyperplasia has been diagnosed in rabbits <1 yr.^2,8

Nowadays, pet rabbits that are presented to a veterinarian are usually not used for breeding. Therefore, signs like reproductive abnormalities that may indicate gynecological disorders are commonly no longer available for the diagnosis of uterine disease. However, typical clinical signs, such as sanguineous vaginal discharge, mammary gland abnormalities, and behavioral changes have been documented in rabbits with uterine adenocarcinoma and endometrial hyperplasia.^1,2 Nevertheless, signs associated with pathological uterine changes in rabbits may be unspecific or subclinical for a long time.⁹

Complications, like the rupturing of the uteri, severe anemia, and adhesions to adjacent viscera, have been described in rabbits with different types of uterine disorders.^1,3,4,10 Occasionally, local metastasis in the peritoneal cavity or distant metastases in lung, liver, bone, and cerebral tissues have been recorded in rabbits with uterine adenocarcinoma.^2,11,12

With the exception of very few retrospective studies, reports of pet rabbits with uterine disorders are mainly case studies.^1,2,9,13 Until now, the clinical outcome of pet rabbits with uterine disease has been recorded in only two studies in English-language journals.^1,2 Therefore, clinical knowledge is primarily based on empirical data.

The purpose of this study was to evaluate histopathological findings of the uteri of pet rabbits after ovariohysterectomy or as a part of necropsy. When data were available, clinical findings, diagnostic workup, treatment, and outcome were assessed.

Materials and Methods

Fifty pet rabbits with confirmed histopathological changes of the uterus that were presented between March 2001 and July 2007 were included in this retrospective study. Thirty-one of the 50 rabbits had suspicious signs of uterine disorders during clinical examination, whereas uterine changes in the other 19 rabbits were not detected before a postmortem examination was performed. All 50 rabbits were assessed, taking into consideration the age of animals and the incidence of different types of uterine disorders. In 19 rabbits, only the results of the histopathological examination were evaluated, whereas data from medical records of 31 rabbits included history, physical examination, diagnostic workup, treatment, and outcome.

Inclusion criteria for the 31 rabbits with suspected uterine disorders were a serosanguineous vaginal discharge and/or an enlarged uterus detected by palpation or diagnostic imaging. Clinical records were studied for specific and unspecific predominant clinical signs such as abdominal pain, enlargement of the abdomen, mammary gland disorders, dyspnea, inappetence, lethargy, and lack of cecotrophy/diarrhea.

Further diagnostic workup in the rabbits with a clinically suspected uterine disorder included diagnostic imaging using abdominal ultrasonography (28 out of 31 rabbits), abdominal radiographs (6 out of 31 rabbits), and thoracic radiographs (3 out of 31 rabbits). Ultrasonographic examinations of the abdomen were performed with an ultrasound unit^a, using a 10 MHz small parts curved-array transducer with the rabbits in either dorsal or lateral recumbency. Abdominal radiographs were performed in right lateral and ventrodorsal views with a special focus on the occurrence of calcifications within the uterus. In case of dyspnea, thoracic radiographs were taken in the left and the right lateral as well as ventrodorsal views to detect metastases.

Depending on the clinical condition of the rabbits and the owner's request, patients either underwent ovariohysterectomy or were euthanized due to their poor clinical condition. Postoperative care included analgesia (0.2 mg/kg meloxicam^b subcutaneously or orally q 24 hr), fluid and electrolyte substitution^c at a rate of 4 mL/kg/hr IV), as well as enrofloxacin^d (10 mg/kg subcutaneously or orally q 24 hr). In the case of inappetence, rabbits were force-fed with a commercial herbivorous diet^e. Medical records of 23 rabbits that underwent ovariohysterectomy were reviewed to evaluate the 6 mo survival rate.

Results

Twenty-three out of 31 rabbits with suspected uterine disorders underwent ovariohysterectomy, whereas 8 died or were euthanized due to their unstable clinical condition. Eighteen out of 19 pet rabbits in which uterine lesions were detected incidentally during postmortem examination had been euthanized or died for some other reason, while only one had undergone an elective ovariohysterectomy beforehand. Consequently, a total of 26 rabbits underwent necropsy followed by histopathology, whereas 24 rabbits only had a histopathological examination of the surgically removed uterus.

Results of the histopathological examination in 50 rabbits with neoplastic and nonneoplastic uterine disorders have been summarized in Table 1 and Figures 1A–D. The histopathological examination revealed one type of uterine disorders in 41 rabbits (82%), two types in 8 rabbits (16%), and three types in 1 rabbit (2%). Tumorous lesions were found in 34 rabbits (68%).

TABLE 1 Frequency of Histopathologically Confirmed Neoplastic and Nonneoplastic Uterine Disorders in 50 Companion Rabbits that were Presented Between 2001 and 2007

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Uterine adenocarcinoma was detected in 27 out of 50 rabbits. In 22 of those rabbits, an adenocarcinoma was diagnosed alone, whereas in 5 rabbits, a combination of other uterine disorders was demonstrated. In one rabbit, a leiomyosarcoma and endometrial hyperplasia were detected in addition to an adenocarcinoma. Within the nonneoplastic lesions, endometrial hyperplasia (13 out of 50 rabbits) was diagnosed most frequently. Other nontumorous uterine disorders included hydrometra, mucometra, and inflammatory changes of the uterus (Table 1, Figure 2).

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Forty-six rabbits were mixed-breeds and four rabbits were purebreeds (Alaska [n = 1], English lop [n = 1], English spot [n = 1], and New Zealand [n = 1]). The age of all rabbits with confirmed uterine disorders ranged from 0.6 to 10.5 yr (mean, 4.9 yr). Rabbits with a suspected clinical uterine disease (31 out of 50 rabbits) were 1–9.7 yr (mean, 4.7 yr). The mean age of the 34 animals with at least one tumorous lesion of the uterus was 5.5 yr, whereas the mean age of rabbits with nontumorous lesions was 3.5 yr. The student t test revealed a significant difference in mean age between the two groups (P = .002). The mean age of rabbits with an adenocarcinoma (5.55 yr) also differed significantly from the mean age of rabbits with other uterine lesions (4.33 yr, P < .05)]. Comparing the mean age of rabbits with solely endometrial hyperplasia (4.48 yr) to animals with other uterine disorders revealed no significant difference (P = .57). The difference between the mean age of rabbits with a solely diagnosed uterine adenocarcinoma (5.55 yr) and the mean age of patients with endometrial hyperplasia (4.48 yr) was not significant (P = .117).

Out of 31 rabbits with suspected clinical uterine disease, 71% showed serosanguineous vaginal discharge or hematuria and/or an enlarged uterus during abdominal palpation. In 29% of the rabbits in which neither bleeding nor an abdominal palpable mass was detected during the clinical examination, abdominal ultrasonography revealed the diagnosis of a pathologically changed uterus. Other clinical signs or symptoms consistent with uterine disorders have been summarized in Table 2.

TABLE 2 Clinical Signs of 31 Pet Rabbits with Uterine Disorders

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In 28 rabbits with suspected uterine lesions in which an abdominal ultrasonography was performed, the clinical diagnosis was confirmed by ultrasonography. Typical ultrasonographic changes varied depending on the type of uterine disease and were characterized by the accumulation of liquid in the uterus lumen or cysts and masses (or calcifications) within the uterus wall.

Abdominal radiography was performed in 11 out of 50 animals, and in 8 cases, uterine alterations could be detected using that diagnostic method. Calcifications of the uterus were found in three of those rabbits during the radiographic examination (Figure 3). Histopathology revealed adenocarcinoma in one of those patients, leiomyosarcoma in another, and the third rabbit had a combination of adenocarcinoma and leiomyosarcoma. Chest radiographs were performed in three rabbits, revealing lung metastases in one case.

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From 31 rabbits with a suspected clinical uterine disease, 8 rabbits (25.8%) either died within a short period or were euthanized immediately after the diagnosis and 23 rabbits (74.2%) underwent ovariohysterectomy. Two rabbits died intraoperatively and two more died within 1 wk of surgery. Of the remaining 19 rabbits, follow-up examinations were not available for 3 animals. The remaining 16 rabbits survived for >6 mo after surgery had been performed.

Metastases were detected in 8 out of 50 rabbits. Two of the rabbits were still alive at the time the metastases were diagnosed, and the primary tumor was found to be a uterine adenocarcinoma in both cases. In one of those rabbits, pulmonary metastases were detected radiographically. In the other rabbit showing right hind limb lameness 3 mo after ovariohysterectomy, an osteolytic area within the tibial plateau indicating neoplastic alterations was detected radiographically. Thus, a bone biopsy was performed and histopathological examination revealed the diagnosis of a carcinoma. In six rabbits, metastases were not found before the postmortem examination. In all of those rabbits, histopathological examination of the uterus revealed adenocarcinoma. Two of those rabbits only had pulmonary metastases. In four rabbits, metastases were detected in ≥2 internal organs. Metastases were detected in the lungs (19.2%), liver (11.2%), kidney (7.7%), and other tissues (11.5%) of 26 rabbits undergoing postmortem examinations.

Discussion

In the present study, neoplastic uterine lesions were predominating nontumorous disorders of the uterus. Of the tumorous lesions, adenocarcinomas were clearly dominant, but neoplastic changes such as leiomyoma, leiomyosarcoma, adenoma, and hemangioma were diagnosed sporadically as well (Table 1). In one case, uterine adenocarcinoma was accompanied by a squamous cell carcinoma, a finding that has also been observed by other authors.² Endometrial hyperplasia comprised >50% of the nonneoplastic uterine lesions. Those findings are consistent with a previously published report in which adenocarcinoma was the most commonly diagnosed uterine disorder followed by endometrial hyperplasia.⁹ Other studies revealed similar results except that endometrial hyperplasia was slightly overrepresented compared to uterine adenocarcinoma.^1,2 In contrast to dogs, in which pyometra is known as a common uterine disorder, only three rabbits in the current study had inflammatory changes of the uterus.^14,15 Other reports where this condition (pyometra) was only sporadically reported in pet rabbits confirm the current study's findings.^1,2,16,17 However, in reproductive females from commercial rabbit farms, pyometra is documented more often than nonreproductive pet rabbits.¹⁸ As reported in the current study where five animals suffered from either hydro- or mucometra, the intrauterine accumulation of sterile fluid is documented infrequently in rabbits but seems to occur more often than in dogs and cats.^1,3,4,19,20 In 18% of included rabbits, two or three different types of uterine lesions were diagnosed. In accordance with those findings, the concomitant occurrence of different kinds of uterine disorders has been observed by other authors as well.^1,2 Mostly, uterine adenocarcinomas were accompanied by endometrial hyperplasia.^1,2,10

The age of rabbits with uterine lesions ranged from 0.6 to 10.5 yr. Consequently, uterine disorders in rabbits can occur at any age, which has also been observed in another study.² The mean age of 4.9 yr in the current study confirm the findings of other authors who detected that rabbits 4–5 yr were most predisposed to uterine disorders.¹ As might be expected, the mean age of animals with nontumorous lesions included in the current study was significantly lower than that of rabbits with neoplastic changes of the uterus.

Serosanguineous vaginal discharge and a palpable mass in the caudal abdomen were the most commonly observed clinical signs in rabbits in the current study. Those findings are similar to several other studies and might therefore be considered a cardinal symptoms of rabbits with uterine disorders.^{1,10,11,21,22} In contrast, only 10 out of 59 animals with uterine disorders showed vaginal bleeding in another study.² Consistent with another report, some of the rabbits included in the current study had vaginal hemorrhage only during urination and a history of hematuria.¹ As porphyrin-pigmented urine caused by plant pigment may be mistaken for either hematuria or bloody vulvar discharge, differentiation by urine dipstick or microscopic examination is recommended in ambiguous cases.¹¹

Corresponding with other reports, nonspecific signs such as depression, anorexia, and abdominal pain during palpation were observed in approximately one third of our rabbits.^1,22

Although none of the animals included in the present study showed mammary gland disorders, such findings are frequently associated with uterine disorders in rabbits.^1,2,23 In one study, 31.9% of rabbits with uterine lesions that were evaluated retrospectively suffered from mammary gland abnormalities.¹ According to the literature, cystic mammary glands are primarily detected in rabbits with either endometrial hyperplasia or adenocarcinoma, whereas mammary gland carcinomas are found only in rabbits with uterine adenocarcinomas.²

None of the rabbits with hydro- or mucometra had an enlarged abdomen, whereas a visibly swollen abdomen has been reported in association with this condition by several other authors.^1,3,4,20 Rather than abdominal enlargement, a fluid-filled mass detected by abdominal palpation allowed for the tentative diagnosis of hydro- or mucometra in the cases in the current report. Vaginal discharge was neither observed in rabbits with hydro- or mucometra nor in animals with pyometra or abscesses within the uterine wall.

Five of the rabbits included in this study had uneaten cecotrophs. The reason for incomplete cecotrophy in those animals might be a painful condition due to uterine disorders that arises especially during ingestion of cecotrophs directly from the anus.²⁰ According to observations of a previous report that semi-liquid cecal ingesta can give a misleading clinical impression of diarrhea, uneaten cecotrophs have been initially mistaken for diarrhea by all of the five rabbit owners in the present study.¹⁰

In two out of four patients with dyspnea, lung metastases were confirmed. but the cause for respiratory disorders could not be identified in the remaining two rabbits. In addition to pulmonary metastases, an enlarged abdomen has also been documented to cause dyspnea in rabbits with uterine disorders. Abdominal pain or anemia may be considered as a cause for respiratory distress in rabbits with uterine disease, too.^4,10,19

Suspected clinical uterine abnormalities were confirmed in all of the rabbits by abdominal ultrasound. Ultrasonographic findings included enlargement of uterine diameter, fluid accumulation within the lumen, masses (e.g., nodules), and areas with changes in echogenicity. In accordance with those results, abdominal ultrasonography has been shown to be the most accurate method for the diagnosis of uterine disorders in rabbits.^1,2 Similar to another report, uterine lesions (mainly uterine tumors but endometrial hyperplasia as well) could also be detected radiographically in almost 75% of the rabbits undergoing abdominal radiography.² Sometimes, neoplastic uterine masses contain foci of mineralization that can be detected by abdominal radiography, as was done in three rabbits included in the current study.²²

Out of 23 rabbits that underwent ovariohysterectomy in the current study, 4 were either euthanized or died within 1 wk of surgery and follow-up examination was not available in 3 rabbits. Sixteen out of 20 rabbits (80%) available for follow up were still alive 6 mo after surgery. Similar to those results, 37 out of 47 rabbits (78.7%) that underwent ovariohysterectomy lived for >3 mo in another study.¹ Nevertheless, data in that study were not comparable to the current study because the times of the follow-up examinations were different. Moreover, it was reported that 16 out of 19 rabbits with uterine disorders (mainly adenocarcinoma and endometrial hyperplasia) that underwent ovariohysterectomy were still alive 12 mo later.⁹ In a recently published study, 8 out of 29 rabbits with uterine adenocarcinoma survived ≥22 mo after ovariohysterectomy.²

The four rabbits that either died intraoperatively or were euthanized within 1 wk of surgery were in an unstable clinical condition (i.e., anorexia, lethargy, severe anemia) at the time of initial presentation. Thus, the study authors agree with others and conclude that outcome is mainly influenced by the clinical condition of the rabbit rather than type and extent of uterine lesions.¹

In accordance to other reports, all of the rabbits included in this study in which metastases were detected had uterine adenocarcinomas as a primary tumor.^11,12,20,21 However, metastasis has also been documented in rabbits with uterine leiomyosarcoma or choriocarcinoma.^6,12,23 As observed in the present study, metastasis reportedly affects several organs, including lung, liver, bone, and brain by hematogenous routes.^2,12,13 Beyond that, metastasis to the skin has also been recorded in rabbits with uterine adenocarcinomas.²¹ Similar to one of the rabbits included in the current study showed that hind limb lameness due to uterine adenocarcinoma metastasis of the tibia, lameness of one hind limb because of a pathologic fracture due to endometrial adenocarcinoma metastasis of the femur has been documented.²⁴ Moreover, hypertrophic osteopathy has been reported in a rabbit with uterine adenocarcinoma and pulmonary metastases.²⁵ As metastases were diagnosed in approximately one-quarter (6 out of 26) of the rabbits undergoing necropsy and metastases were mainly detected in the lungs, preoperative diagnostic workup should always include thoracic radiographs. Beyond that, metastases were not detected within the peritoneal cavity during ovariohysterectomy in any of the included rabbits. It has been reported that either metastatic disease or local invasion of peritoneal structures might not be macroscopically apparent during laparotomy or might not be seen on thoracic radiographs at the time of surgery.¹⁰ Moreover, development of uterine adenocarcinoma from a uterine remnant and subsequent metastasis was reported in a Blanc de Hotot rabbit.²⁶ A uterine stump adenocarcinoma in a cat that had undergone ovariohysterectomy at the age of 6 mo shows that the possibility of development of a uterine stump adenocarcinoma is not unique to rabbits.²⁷ Therefore, it is recommended to ligate the uterus at the vaginal side of the cervix when performing an ovariohysterectomy in a rabbit.²⁸ Additionally, re-examination including abdominal ultrasonography and thoracic radiographs at regular intervals (3–6 mo) is recommended for a period of 1–2 yr after ovariohysterectomy.^2,10

Conclusion

Uterine adenocarcinoma and endometrial hyperplasia are the most prominent uterine disorders in pet rabbits. The clinical diagnosis in rabbits with uterine disease relies on clinical signs (e.g., serosanguineous vaginal discharge, hematuria, palpation of an enlarged and/or irregular uterus in the caudoventral part of the abdomen). To confirm uterine disorders, ultrasonography of the abdomen is recommended. The treatment of choice is ovariohysterectomy in clinically stable patients. Rabbits in a poor clinical condition have a grave prognosis and should be euthanized if preoperative stabilization is not possible. Metastatic disease may either not be apparent during laparotomy or may not be identified on thoracic radiographs at the time of surgery. In female pet rabbits not intended for breeding, either ovariohysterectomy should be performed at an early age or routine examinations including ultrasonography of the abdomen are recommended on a regular basis.