Assessment of reported uterine lesions diagnosed histologically after ovariohysterectomy in 1,928 pet rabbits (Oryctolagus cuniculus)

Kanako Settai Laboratory of Veterinary Pathology, College of Bioresource Sciences, Nihon University, Fujisawa, Kanagawa, 252-0880, Japan.

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Hirotaka Kondo Laboratory of Veterinary Pathology, College of Bioresource Sciences, Nihon University, Fujisawa, Kanagawa, 252-0880, Japan.

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Hisashi Shibuya Laboratory of Veterinary Pathology, College of Bioresource Sciences, Nihon University, Fujisawa, Kanagawa, 252-0880, Japan.

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Abstract

OBJECTIVE

To assess variations in age, breed, and clinical signs in rabbits with neoplastic or nonneoplastic uterine lesions and to investigate potential relationships between endometrial adenocarcinoma and age at ovariohysterectomy or breed in rabbits.

ANIMALS

1,928 rabbits that underwent ovariohysterectomy for treatment or prevention of possible uterine disease.

PROCEDURES

With an online questionnaire distributed to 441 veterinary hospital members of the Japanese Society of Exotic Pet Medicine, data were retrospectively collected regarding age, breed, and findings on physical and histologic examinations for pet rabbits that underwent ovariohysterectomy between January 1, 2009, and April 30, 2018. Rabbits were grouped by reported age, breed, clinical signs, and uterine lesions, and results were assessed across groups. Logistic regression analysis was used to identify potential relationships between endometrial adenocarcinoma and breed or age at ovariohysterectomy in rabbits.

RESULTS

The questionnaire response rate was 9.8% (43/441), with data reported for 1,928 rabbits (mixed breed, 600 [31.1%]; Netherland Dwarf, 520 [27.0%]; Holland Lop, 286 [14.8%]; or various other breeds, 522 [27.1%]). The most commonly reported neoplastic and nonneoplastic lesions were endometrial adenocarcinoma (1,035/1,928 [53.7%]) and endometrial hyperplasia (842 [43.7%]), respectively, and the most commonly reported clinical sign was hematuria or serosanguineous vaginal discharge (1,020/1,928 [52.9%]). As age at ovariohysterectomy increased, so did the odds (OR, 1.826; 95% CI, 1.640 to 2.033) of uterine adenocarcinoma.

CONCLUSIONS AND CLINICAL RELEVANCE

Results supported ovariohysterectomy in rabbits before 2 years of age as a key preventative measure to mitigate uterine disease, particularly endometrial adenocarcinoma.

Abstract

OBJECTIVE

To assess variations in age, breed, and clinical signs in rabbits with neoplastic or nonneoplastic uterine lesions and to investigate potential relationships between endometrial adenocarcinoma and age at ovariohysterectomy or breed in rabbits.

ANIMALS

1,928 rabbits that underwent ovariohysterectomy for treatment or prevention of possible uterine disease.

PROCEDURES

With an online questionnaire distributed to 441 veterinary hospital members of the Japanese Society of Exotic Pet Medicine, data were retrospectively collected regarding age, breed, and findings on physical and histologic examinations for pet rabbits that underwent ovariohysterectomy between January 1, 2009, and April 30, 2018. Rabbits were grouped by reported age, breed, clinical signs, and uterine lesions, and results were assessed across groups. Logistic regression analysis was used to identify potential relationships between endometrial adenocarcinoma and breed or age at ovariohysterectomy in rabbits.

RESULTS

The questionnaire response rate was 9.8% (43/441), with data reported for 1,928 rabbits (mixed breed, 600 [31.1%]; Netherland Dwarf, 520 [27.0%]; Holland Lop, 286 [14.8%]; or various other breeds, 522 [27.1%]). The most commonly reported neoplastic and nonneoplastic lesions were endometrial adenocarcinoma (1,035/1,928 [53.7%]) and endometrial hyperplasia (842 [43.7%]), respectively, and the most commonly reported clinical sign was hematuria or serosanguineous vaginal discharge (1,020/1,928 [52.9%]). As age at ovariohysterectomy increased, so did the odds (OR, 1.826; 95% CI, 1.640 to 2.033) of uterine adenocarcinoma.

CONCLUSIONS AND CLINICAL RELEVANCE

Results supported ovariohysterectomy in rabbits before 2 years of age as a key preventative measure to mitigate uterine disease, particularly endometrial adenocarcinoma.

The domestic rabbit (Oryctolagus cuniculus) originated from the European wild rabbit, and 49 breeds of rabbits are now recognized by the American Rabbit Breeders Association.1 Rabbits are popular pets in Japan and other countries, and recent reports2–8 have described uterine disease in rabbits. For instance, endometrial adenocarcinoma and endometrial hyperplasia are common uterine diseases in rabbits, and recent retrospective studies6–8 of uterine tumors in rabbits show that endometrial adenocarcinoma is more common than leiomyoma or leiomyosarcoma. Other less common uterine tumors, such as choriocarcinoma9 and malignant Müllerian tumor,3 have also been described in rabbits. Uterine disease in rabbits generally progresses slowly, and affected rabbits may develop clinical signs of lethargy, anorexia, hematuria, serosanguineous vaginal discharge, mammary gland abnormalities, or urethral obstruction.10 In addition, uterine tumors in rabbits may metastasize in 1 to 2 years to the lungs, liver, brain, or bone, alone or in combination.10 However, to our knowledge, there has been no large-scale retrospective study of > 1,000 rabbits with uterine disease. The objectives of the study reported here were to assess variations in age, breed, and clinical signs in rabbits with neoplastic or nonneoplastic uterine lesions and to investigate potential relationships between endometrial adenocarcinoma and age at ovariohysterectomy or breed in rabbits.

Materials and Methods

Animals

Inclusion criteria for our retrospective study were rabbits that underwent ovariohysterectomy between January 1, 2009, and April 30, 2018, because of potential uterine disease or for disease-prevention purposes and for which subsequent histologic examinations had been performed on the removed uterus. Rabbits were eligible for inclusion even if no abnormal clinical signs were evident before ovariohysterectomy.

Data collection

To gather information on rabbits that underwent ovariohysterectomy, a questionnaire was developed and distributed to veterinary hospitals that belonged to the JSEPM. For each rabbit that underwent ovariohysterectomy, respondent veterinary hospitals were asked to provide the rabbit's breed, age at ovariohysterectomy, clinical signs before surgery, and results of histologic examination of the removed uterus. Respondents provided their answers in a spreadsheet,a which they completed and then submitted through the JSEPM website. The questionnaire response collection period was open from April 1 to May 31, 2018.

Breeds—Rabbit breeds were classified on the basis of the 49 breeds recognized by the American Rabbit Breeders Association1 when the questionnaire was developed. For rabbits that respondents did not report a breed or reported it as unknown, the breed was assigned as unknown. Because mini-rabbit was a common name in Japan for mixed-breed rabbits of the Japanese white breed or Dutch breeds, rabbits reported as such were assigned the general term mixed breed.

Age—Rabbits were also grouped by reported age at ovariohysterectomy in 1-year increments. When age was reported as unknown or a respondent did not provide an age (the answer in the questionnaire was left blank), the age of the rabbit was recorded as unknown. Rabbits with unknown age were not included in regression analysis but were included in calculations for proportions of affected rabbits and depictions of frequency distributions of clinical signs and uterine lesions identified.

Clinical signs—Clinical signs were compiled overall and for rabbits grouped on the basis of neoplastic versus nonneoplastic lesions. For rabbits that respondents did not input questionnaire responses for clinical signs (the answer field in the questionnaire was left blank), the clinical signs of such rabbits were recorded as unknown.

Histologic examination—To be included in the study, each rabbit also had to have results reported for histologic examination of its removed uterus. Histologic diagnoses of adenocarcinoma, uterine adenocarcinoma, or endometrial adenocarcinoma were grouped under the collective term endometrial adenocarcinoma. Histologic diagnoses of endometrial hyperplasia, endometrial cystic hyperplasia, or endometrial papillary hyperplasia were grouped under the collective term endometrial hyperplasia.

Statistical analysis

Available softwareb was used to perform all statistical analyses, and values of P < 0.05 were considered significant. The Kolmogorov-Smirnov test was used to determine whether data for continuous variables were normally distributed (values of P ≥ 0.05 indicated normal distribution). Differences in mean age for groups of rabbits with different types of uterine lesions were assessed with the Welch t test (for normally distributed data) or the Mann-Whitney U test (for nonnormally distributed data), and values of P ≤ 0.05 were considered significant. Logistic regression analysis was used to identify potential relationships between endometrial adenocarcinoma and rabbit age at ovariohysterectomy or breed. The Hosmer-Lemeshow test was used to assess the goodness of fit of the logistic regression models, with values of P ≥ 0.05 indicating no evidence of poor fit. Odds ratios and Wald χ2 values were calculated for variables in the final model.

Results

Animals

The survey was distributed to 441 veterinary hospitals, and 43 (9.8%) responded with clinical and histologic information on 1,928 rabbits that underwent ovariohysterectomy between January 1, 2009, and April 3, 2018. Age at ovariohysterectomy was reported for 1,884 of the 1,928 (97.7%) rabbits, and the median age was 59 months (range, 6 to 144 months). Rabbits were reported as mixed breed (600/1,928 [31.1%]), Netherland Dwarf (520 [27.0%]), Holland Lop (286 [14.8%]), or various other breeds (522 [27.1%]).

Clinical signs

Respondents reported that, before ovariohysterectomy, abnormal clinical signs were evident in 1,391 of the 1,928 (72.1%) rabbits but not in 372 (19.3%) rabbits. Respondents did not comment regarding clinical signs for the remaining rabbits (165/1,928 [8.6%]). Hematuria or serosanguineous vaginal discharge was the most commonly reported clinical sign overall (1,020/1,928 [52.9%]), regardless of age (Figure 1). The most common uterine lesions reported for rabbits with hematuria or serosanguineous vaginal discharge were endometrial adenocarcinoma (574/1,020 [56.3%]) and endometrial hyperplasia (380/1,020 [37.3%]; Figure 2).

Figure 1—
Figure 1—

Frequency distribution of clinical signs, grouped as hematuria or serosanguineous vaginal discharge (red; n = 1,020), anorexia (yellow; 272), mammary gland abnormality (black; 116), all other abnormal clinical signs (gray; 157), or no abnormal clinical signs (green; 372), in 1,763 of 1,928 pet rabbits before ovariohysterectomy and histologic examination between January 1, 2009, and April 30, 2018, and grouped by age at ovariohysterectomy, as reported by JSEPM-member veterinary hospital respondents to a questionnaire open from April 1 to May 31, 2018. Respondents did not comment on clinical signs for the remaining 165 rabbits (blue). Rabbits for which respondents did not indicate age at ovariohysterectomy were grouped together (ND). ND = Age at ovariohysterectomy was not documented by respondent.

Citation: Journal of the American Veterinary Medical Association 257, 10; 10.2460/javma.2020.257.10.1045

Figure 2—
Figure 2—

Frequency distribution of endometrial adenocarcinoma (black; n = 574), endometrial hyperplasia (blue; 380), or other uterine lesions (gray; 66) reported for the 1,020 rabbits described in Figure 1 with hematuria or serosanguineous vaginal discharge and grouped by age at ovariohysterectomy. See Figure 1 for remainder of key.

Citation: Journal of the American Veterinary Medical Association 257, 10; 10.2460/javma.2020.257.10.1045

For the 372 rabbits reported not to have had abnormal clinical signs before ovariohysterectomy, respondents indicated that 90 rabbits underwent ovariohysterectomy for disease-prevention purposes and that uterine abnormalities (eg, uterine mass and enlargement) were detected during surgery. Respondents also reported that among these 372 rabbits, uterine abnormalities had been detected by palpation, radiographic examination, or ultrasonography on preoperative examination for ovariohysterectomy or laparotomy scheduled for reasons other than uterine disease. Histologic examination of tissue sections from uteri removed from these 372 rabbits revealed uterine lesions that were neoplastic (eg, endometrial adenocarcinoma, n = 182 [48.9%]; leiomyoma, 35 [9.4%]; or leiomyosarcoma, 17 [4.6%]) or nonneoplastic (eg, endometrial hyperplasia, 157 [42.2%]; adenomyosis, 21 [5.6%]; or endometrial venous aneurysm, 8 [2.2%]), alone or in combination. Most of these rabbits (366/372 [98.4%]) had ≥ 2 types of uterine lesions identified.

Uterine lesions

When rabbits were grouped by reported uterine lesions identified on histologic examination, 1,900 of the 1,928 (98.5%) rabbits had 2,523 uterine lesions, and 631 of these 1,900 (33.2%) rabbits had ≥ 2 types of lesions. Of these 1,900 rabbits, 1,225 were reported to have had 1,384 neoplastic lesions (Figure 3), and 996 were reported to have had 1,139 nonneoplastic lesions (Figure 4), with some rabbits reported to have had neoplastic and nonneoplastic uterine lesions.

Figure 3—
Figure 3—

Frequency distribution of the 1,384 neoplastic uterine lesions, grouped as endometrial adenocarcinoma (black [n = 1,035]), leiomyoma (orange [165]), leiomyosarcoma (purple [75]), endometrial adenoma (yellow [32]), hemangioma (green [29]), carcinosarcoma (red [28]), or all other neoplastic uterine lesions (gray [20]), reported for the 1,225 affected rabbits described in Figure 1 and grouped by age at ovariohysterectomy. See Figure 1 for remainder of key.

Citation: Journal of the American Veterinary Medical Association 257, 10; 10.2460/javma.2020.257.10.1045

Figure 4—
Figure 4—

Frequency distribution of the 1,139 nonneoplastic uterine lesions, grouped as endometrial hyperplasia (blue [n = 842]), adenomyosis (green [108]), venous aneurysms (red [73]), endometritis (yellow [35]), hematoma (purple [33]), hydrometra (orange [14]), or all other nonneoplastic uterine lesions (gray [34]), reported for the 996 affected rabbits described in Figure 1 grouped by age at ovariohysterectomy. See Figure 1 for remainder of key.

Citation: Journal of the American Veterinary Medical Association 257, 10; 10.2460/javma.2020.257.10.1045

Neoplastic lesions—Overall, in the 1,900 rabbits with uterine lesions, the most commonly reported uterine neoplasms were endometrial adenocarcinoma (1,035/1,900 [54.5%] rabbits; 1,035/1,384 [74.8%] neoplastic lesions), leiomyoma (165/1,900 [8.7%] rabbits; 165/1,384 [11.9%] neoplastic lesions), leiomyosarcoma (75/1,900 [3.9%] rabbits; 75/1,384 [5.4%] neoplastic lesions), endometrial adenoma (32/1,900 [1.7%] rabbits; 32/1,384 [2.3%] neoplastic lesions), hemangioma (29/1,900 [1.5%] rabbits; 29/1,384 [2.1%] neoplastic lesions), or carcinosarcoma (28/1,900 [1.5%] rabbits; 28/1,384 [2.0%] neoplastic lesions), alone or in combination (Figure 3). Of the 1,035 rabbits with endometrial adenocarcinoma, 642 (62.0%) had endometrial adenocarcinoma alone, 77 (7.4%) had concurrent leiomyoma, 32 (3.1%) had concurrent leiomyosarcoma, 36 (3.5%) had various other concurrent neoplastic lesions, and 248 (24.0%) had concurrent nonneoplastic lesions.

Age at ovariohysterectomy was reported for 642 rabbits with endometrial adenocarcinoma alone (Table 1). The mean ± SD age at ovariohysterectomy was 67.2 ± 19.2 months (median, 67 months; range, 6 to 131 months) for rabbits with endometrial adenocarcinoma alone, with those in the age category of 60 to < 72 months reported most commonly (161/642 [25.1%]). The youngest rabbit with endometrial adenocarcinoma was a 6-month-old Netherland Dwarf with hematuria. When the 2 most commonly reported breeds of rabbits were considered, endometrial adenocarcinoma was reported in 265 of the 520 (51.0%) Netherland Dwarf rabbits and in 168 of the 286 (58.7%) Holland Lop rabbits. Common clinical signs reported for the 1,035 rabbits with endometrial adenocarcinoma included hematuria or serosanguineous vaginal discharge (n = 574 [55.5%]), anorexia (272 [26.3%]), mammary gland abnormalities (116 [11.2%]), lethargy (38 [3.7%]), or anemia (26 [2.5%]), alone or in combination. Many rabbits were reported to have had ≥ 2 abnormal clinical signs, and most rabbits with anemia also had hematuria (20/26 [76.9%]).

Table 1—

Distribution by age at ovariohysterectomy and breed (ie, Netherland Dwarf, Holland Lop, or other breeds) of pet rabbits with endometrial adenocarcinoma alone (n = 642) or endometrial hyperplasia alone (440) diagnosed between January 1, 2009, and April 30, 2018, among 1,884 rabbits for which age at ovariohysterectomy, breed, and histologic examination results were reported by JSEPM-member veterinary hospital respondents to a questionnaire open from April 1 to May 31, 2018.

 Rabbits with EA aloneRabbits with EH alone
 No. of rabbits by breed group No. of rabbits by breed group 
Age (mo)NDHLOther breedsTotal (%)NDHLOther breedsTotal (%)
< 121001 (0.1)1113 (0.2)
12 to < 240011 (0.1)12152653 (2.8)
24 to < 3662412 (0.6)19155185 (4.5)
36 to < 488163458 (3.1)24105993 (4.9)
48 to < 60273172130 (6.9)2983269 (3.7)
60 to < 72393191161 (8.5)2423056 (3.0)
72 to < 84382478140 (7.4)1103243 (2.3)
84 to < 9622105284 (4.5)821323 (1.2)
96 to < 1081321732 (1.7)4048 (0.4)
108 to < 12051814 (0.7)1045 (0.3)
≥ 1202079 (0.5)1102 (0.1)
Total161117364642 (34.1)13454252440 (23.4)

EA = Endometrial adenocarcinoma. EH = Endometrial hyperplasia. HL = Holland Lop. ND = Netherland Dwarf.

Nonneoplastic lesions—Overall, in the 1,900 rabbits with uterine lesions, the most commonly reported nonneoplastic uterine lesions were endometrial hyperplasia (842/1,900 [44.3%] rabbits; 842/1,139 [73.9%] nonneoplastic lesions), adenomyosis (108/1,900 [5.7%] rabbits; 108/1,139 [9.5%] nonneoplastic lesions), venous aneurysms (73/1,900 [3.8%] rabbits; 73/1,139 [6.4%] nonneoplastic lesions), endometritis (35/1,900 [1.8%] rabbits; 35/1,139 [3.1%] nonneoplastic lesions), hematoma (33/1,900 [1.7%] rabbits; 33/1,139 [2.9%] nonneoplastic lesions), or hydrometra (14/1,900 [0.7%] rabbits; 14/1,139 [1.2%] nonneoplastic lesions), alone or in combination (Figure 4). Pyometra was only reported in 5 of the 1,900 (0.3%) rabbits that had uterine lesions.

Age at ovariohysterectomy was reported for 440 rabbits with endometrial hyperplasia alone (Table 1). The mean ± SD age at ovariohysterectomy was 47.2 ± 22.9 months (median, 47 months; range, 8 to 132 months) for rabbits with endometrial hyperplasia alone (n = 440), with those in the age category of 36 to < 48 months reported most common (93/440 [21.1%]). In addition, venous aneurysms were identified most commonly in rabbits in the age categories of 24 to < 36 months (15/73 [20.5%]) and 36 to < 48 months (14/73 [19.2%]). Thirty-five of the 73 (47.9%) rabbits with venous aneurysm also had concurrent endometrial hyperplasia (Figure 4). When the 2 most commonly reported breeds of rabbits were considered, endometrial hyperplasia was identified in 234 of the 520 (45.0%) Netherland Dwarf rabbits and 111 of the 286 (38.8%) Holland Lop rabbits. Common clinical signs reported for rabbits with endometrial hyperplasia included hematuria or serosanguineous vaginal discharge (380/842 [45.1%]) and anorexia (113/842 [13.4%]).

Results compared between groups

Results of the Kolmogorov-Smirnov test of age at ovariohysterectomy were compiled for rabbits grouped by breed and by whether endometrial adenocarcinoma alone versus endometrial hyperplasia alone had been diagnosed (Table 2). Most results were not normally distributed. The mean ± SD age at ovariohysterectomy was significantly (Mann-Whitney U test z value = −14.305; P ≤ 0.001) older for rabbits with endometrial adenocarcinoma alone (67.15 ± 19.19 months) versus endometrial hyperplasia alone (47.23 ± 22.87 months). The mean ± SD age at ovariohysterectomy in rabbits with endometrial adenocarcinoma alone was significantly (Mann-Whitney U test z value = −3.279; P ≤ 0.001) older for Netherland Dwarf rabbits (69.57 ± 20.48 months), compared with Holland Lop rabbits (62.06 ± 15.56 months). Similarly, the mean ± SD age at ovariohysterectomy in rabbits with endometrial hyperplasia alone was significantly (Mann-Whitney U test z value = −4.766; P ≤ 0.001) older for Netherland Dwarf rabbits (50.91 ± 22.37 months), compared with Holland Lop rabbits (35.22 ± 20.82 months).

Table 2—

Results of Kolmogorov-Smirnov test analysis to determine normality of data for results of reported age at ovariohysterectomy for the rabbits described in Table 1, grouped as all breeds (n = 1,884), Netherland Dwarf (295), or Holland Lop (171) and reported to have had endometrial adenocarcinoma alone or endometrial hyperplasia alone.

  Age (mo) 
LesionRabbitsMean ± SDMedianIQRP value*
EA aloneAll rabbits67.15 ± 19.1966.0054–79< 0.001
 ND69.57 ± 20.4870.0059–840.200
 HL62.36 ± 16.0361.0049–720.033
EH aloneAll rabbits47.23 ± 22.8744.0029–60< 0.001
 ND50.91 ± 22.3748.0036–620.031
 HL35.22 ± 20.8329.0021–450.004

Kolmogorov-Smirnov test values of P ≥ 0.05 indicated normal distribution.

IQR = Interquartile (25th to 75th percentile) range.

See Table 1 for remainder of key.

Logistic regression analysis

Results for the variables of age at ovariohysterectomy and breed were entered into the logistic regression model for endometrial adenocarcinoma. Results of the Hosmer-Lemeshow goodness-of-fit test for logistic regression were not significant (P = 0.51) and thus indicated that the model fit the data well. As age at ovariohysterectomy increased, so did the odds (OR, 1.826; 95% CI, 1.640 to 2.033; P < 0.001) of endometrial adenocarcinoma. In addition, Netherland Dwarf rabbits had lower odds (OR, 0.380; 95% CI, 0.259 to 0.557; P < 0.001) of endometrial adenocarcinoma, compared with Holland Lop rabbits.

Discussion

Similar to findings of other studies,6–8 results of the present study indicated that the most commonly reported neoplastic and nonneoplastic uterine lesions in rabbits were endometrial adenocarcinoma and endometrial hyperplasia, respectively. When rabbits in the present study were grouped by age, the proportion of rabbits with endometrial adenocarcinoma alone was generally higher for age groups ≥ 36 months; however, the youngest rabbit with endometrial adenocarcinoma was a 6-month-old Netherland Dwarf with hematuria. Although adenomas have previously been reported8,10 as the second-most common uterine tumor among pet rabbits, our findings indicated that endometrial adenoma ranked fourth (following endometrial adenocarcinoma, leiomyoma, and leiomyosarcoma) among neoplastic uterine lesions reported for rabbits in the present study. Furthermore, given the fact that 2 different types of tumors identified concurrently in rabbits have rarely been reported,4,5 our findings indicated more rabbits with ≥ 2 different types of tumors (eg, endometrial adenocarcinoma and leiomyoma [165/1,928 {8.6%}] or leiomyosarcoma [75/1,928 {3.9%}]) than we expected.

Consistent with previous reports,8,10 the most common nonneoplastic lesion identified in rabbits of the present study was endometrial hyperplasia (842/1,928 [43.7%]). However, our findings of adenomyosis (108 [5.6%]) and venous aneurysms (73 [3.8%]) as the next most common nonneoplastic lesions differed with results from a previous study10 in 47 pet rabbits that indicate hydrometra (6/25 [24%]) was the second-most common. In the present study, however, hydrometra was ranked as the sixth-most commonly reported nonneoplastic lesion (14/1,900 [0.7%]).

Results of the present study indicated that age at ovariohysterectomy was associated with endometrial adenocarcinoma in that as age at ovariohysterectomy in rabbits increased, so did the odds (OR, 1.826) of endometrial adenocarcinoma. In addition, the mean age at ovariohysterectomy was older for rabbits with endometrial adenocarcinoma alone, compared with endometrial hyperplasia alone, and with each condition, the mean age was older for Netherland Dwarf rabbits, compared with Holland Lop rabbits. Interestingly, the odds (OR, 0.380) of endometrial adenocarcinoma was lower for Netherland Dwarf rabbits, compared with Holland Lop rabbits. However, Holland Lop rabbits with endometrial adenocarcinoma or hyperplasia underwent ovariohysterectomy at younger ages, the reason for which could not be determined from the present study. Nonetheless, our findings supported ovariohysterectomy at early ages in rabbits.

Similar to previous reports,8,10 hematuria or serosanguineous vaginal discharge (1,020/1,928 [52.9%]) was the most common clinical sign in rabbits with neoplastic or nonneoplastic uterine lesions in the present study. However, hematuria in female rabbits has been associated with uterine lesions, renal infarction, pyelonephritis, cystitis, and urolithiasis.11 Thus, it is important to differentiate uterine diseases from other underlying causes of hematuria in rabbits. Interestingly, anemia was reported in 26 rabbits, all of which had endometrial adenocarcinoma and 20 of which also had hematuria. However, anemia and death may also occur with nonneoplastic uterine disease, such as endometrial venous aneurysms.11–13

A limitation of the present study was that the response rate to our questionnaire was only 9.8% (43/441). We attributed the low response rate to the short collection period of 2 months and to the fact that the questionnaire was online. Another limitation was case selection bias toward small or dwarf breeds or crosses because of their popularity as pets in Japan.14 Therefore, information on other breeds was limited in the present study. However, in small or dwarf breeds or crosses, our findings supported recommendations15 for ovariohysterectomy in rabbits before 2 years of age, and preferably between 6 and 9 months of age, to prevent uterine disease, particularly endometrial adenocarcinoma. In addition, findings of the present study underscored the need to perform careful gross examination of the uterus during ovariohysterectomy in rabbits and subsequent histologic examination of removed uteri, even in rabbits with no abnormal clinical signs. Furthermore, we highly recommend that veterinarians perform routine physical examinations (including abdominal palpation) combined with abdominal ultrasonography to help mitigate uterine disease in rabbits.

Acknowledgments

The authors declare that there were no conflicts of interest.

The authors thank the JSEPM for its assistance in distributing the questionnaire and providing respondents a means to submit their response.

Footnotes

a.

Microsoft Excel, version 2003, Microsoft Corp, Redmond, Wash.

b.

SPPS, version 26, IBM Corp, Armonk NY.

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