Thymomas in Rabbits: Clinical Evaluation, Diagnosis, and Treatment
Thymomas are rarely recorded in rabbits, and the literature includes comparatively few cases. Medical records were reviewed to identify all pet rabbits in which a mediastinal mass was diagnosed between Feb 2007 and Jan 2010. Signalment, history, clinical signs, diagnostic work-up (including laboratory data, diagnostic imaging, and ultrasound-guided fine-needle aspiration of the mediastinal mass), treatment modalities, survival time, and histologic findings were evaluated. Cytologic and/or histopathologic examinations revealed thymomas in all rabbits with mediastinal masses (n=13). Rabbits with thymomas showed clinical signs of dyspnea (76.9%), exercise intolerance (53.9%), and bilateral exophthalmos (46.2%). In seven rabbits the thymoma was removed surgically. Two rabbits were treated conservatively, and four rabbits were euthanized because of their poor clinical condition. The two rabbits that underwent surgery were euthanized 6 mo and 34 mo later. Mediastinal masses in rabbits appear to be more common than previously believed and consist primarily of thymomas rather than thymic lymphomas. Cytology of samples collected by ultrasound-guided fine-needle aspiration is an accurate diagnostic tool for the identification of thymomas in rabbits. Due to a high rate of perioperative mortality, intensive perioperative care and the provision of a low-stress environment are recommended for a successful thoracotomy.
Introduction
A thymoma is a neoplasm in the cranial mediastinum. Thymomas are composed of thymic epithelium and normally include various degrees of benign lymphocytic infiltrations. In domestic animals, the masses are largely restricted to the cranial mediastinum but they may extend from the neck to the caudal mediastinum. Thymomas are usually nodular and encapsulated, causing compression of adjacent tissues.1 Although the disease is rarely documented, it has been reported in dogs and cats, as well as in cattle, goats, sheep, pigs, horses, ferrets, rats, and humans.1–3
To date, information about rabbits with thymomas mainly stems from clinical reports.4–11 Apart from thymomas, thymic lymphomas and mediastinal abscesses should also be considered as possible causes of mediastinal masses in rabbits.12–14 Main indications associated with an intrathoracic mass include dyspnea, exercise intolerance, and bilateral exophthalmos.4,6,9 Various treatment options for rabbits diagnosed with thymomas have been proposed, including surgery, chemotherapy, and radiation therapy.9
The rationale underlying this study is that, according to the authors’ experiences, mediastinal masses, especially thymomas, often remain unrecognized in rabbits with respiratory distress and/or exercise intolerance. Furthermore, the authors hypothesize that mediastinal masses in this species are predominantly represented by thymomas rather than by thymic lymphomas. The purpose of the study was to evaluate clinical findings, diagnostic work-up, treatment options, and the outcome of rabbits with thymomas.
Materials and Methods
Case Selection
Medical records from the Small Animal Clinic at the Animal Hospital of the University of Veterinary Medicine Vienna (Austria) were reviewed from Feb 2007 to Jan 2010 to identify all rabbits in which mediastinal masses had been diagnosed. All pet rabbits with a clinically recognized cranial mediastinal mass and subsequent cytology and/or histology results were included in the study.
Diagnostic Work-up
Diagnostic work-up of the rabbits with a suspected mediastinal mass included case history, clinical examination, and diagnostic imaging with thoracic radiographs (n=12) and/or ultrasonography (n=12). Thoracic radiographs were taken in left lateral and dorsoventral views. Ultrasound examinations were performed with an ultrasound unita, employing a 5–8 MHz small parts curved-array transducer in a bilateral intercostal approach with the rabbits in either sternal or lateral recumbency. Ultrasound-guided fine-needle aspiration (FNA) of the mediastinal mass (n=11) or thoracocentesis of pleural effusion (n=1) was performed and evaluated by cytology. FNA of the mass was performed under sedation with intramuscular (IM) midazolamb (1 mg/kg) and medetomidinec (0.2 mg/kg). In eight rabbits, a complete blood cell count was performed and serum biochemistry was analyzed using standard laboratory methodsd,e.
Treatment
Depending on the clinical condition of the rabbit and the owners’ wishes, the following treatment modalities were implemented: surgical removal of the thoracic mass, conservative treatment, and euthanasia.
Histopathology
A histopathologic examination of the surgical removed mediastinal mass was performed in seven rabbits. Furthermore, a necropsy including histopathology was carried out in nine rabbits (five of the seven rabbits that underwent surgery and four rabbits that were immediately euthanized). Thymoma with >50% lymphocytes were classified as lymphocyte predominant and cases with >50% epithelial cells were subcategorized as being epithelial predominant. Cases with approximately 50:50 cells were diagnosed as mixed lymphoepithelial. In cases of lymphocyte predominant thymomas (n=6) where a differentiation between thymoma and thymic lymphoma was difficult, immunohistochemical analysis of cytokeratin expression in paraffin-embedded tissues was performed. Mouse anticytokeratinf was used as the primary antibody.
Results
Signalment, History, and Clinical Signs
Thirteen pet rabbits met the study's inclusion criteria. In all rabbits the mediastinal mass was identified as a thymoma. Nine rabbits were males and four were females. Nine rabbits were mixed-breed rabbits and four were purebreed rabbits of various breeds, including Thüringer (n=1), tan (n=1), and Lionhead (n=2). The ages ranged from 3 yr to 10 yr (median, 6.1 yr).
The histories of 10 of the pet rabbits were available, relating to the duration between the onset of the disease and the time the rabbits were first examined by a veterinarian. An acute onset was observed in three rabbits. Seven owners reported clinical signs lasting for a period of up to 6 mo. The median period of noticeable clinical signs in the rabbits before their presentation was 45 days (Table 1).
Between onset of the disease and time of diagnosis
Typical clinical signs in pet rabbits with a thymoma were dyspnea (n=10), exercise intolerance (n=7), and bilateral transient exophthalmos (n=6). In only two cases was an exophthalmos noticed by the owner before the animal presented to a veterinarian. Symptoms such as lack of appetite, coughing, and bilateral prolapse of the third eyelid were also detected in affected animals. Auscultation of the thorax revealed muffled heart sounds or a heart murmur in four rabbits (Table 2).
Diagnostic Work-up
Hematology and serum biochemistry profiles were performed in eight rabbits. Red blood cell counts showed a mildly decreased hematocrit in five cases. Erythrocytes remained within the reference range. Total protein was moderately elevated in one rabbit. A lymphocytosis was observed in four rabbits. In six of the blood samples, a hyperglycemia was noted. Ca levels were determined in four rabbits and were mildly decreased in one case. Creatinine and alanine aminotransferase were within the reference range (Table 3).
Diagnostic imaging in 12 rabbits included thoracic radiographs and ultrasonography. Thoracic radiographs were almost identical in all cases. The cranial contour of the heart was not visible and the trachea was elevated (Figure 1A). In the dorsoventral view, the entire cranial thorax was opacified, and a soft-tissue mass was suspected (Figure 1B). Ultrasonography of the cranial mediastinum showed a nonuniform, hypoechoic mass cranial to the heart with small to large cystic lesions. The masses were either round, measuring up to 4 cm in diameter (Figure 2), or smaller and crescent-shaped (Figure 3).
Citation: Journal of the American Animal Hospital Association 48, 2; 10.5326/JAAHA-MS-5683
Citation: Journal of the American Animal Hospital Association 48, 2; 10.5326/JAAHA-MS-5683
Citation: Journal of the American Animal Hospital Association 48, 2; 10.5326/JAAHA-MS-5683
An ultrasound-guided FNA of the mass (n=11) or a thoracocentesis of pleural effusion (n=1) was performed. One rabbit was euthanized due to its deteriorating condition before a FNA was taken. Cytology of 10 aspirated samples identified the mass as a thymoma (one sample was nondiagnostic). Cytologically, thymomas were characterized by a mixed population of small and occasional large lymphocytes and various amounts of epithelial cells (Figure 4). In one case it was not possible to differentiate between thymoma and thymic lymphoma by pleural fluid cytology (Table 4).
Citation: Journal of the American Animal Hospital Association 48, 2; 10.5326/JAAHA-MS-5683
Cytology from ultrasound-guided fine-needle aspiration of the mass
Histology from surgically removed mass
Immunohistochemical analysis of cytokeratin expression was performed.
Histology from postmortem examination
Cytology from pleural effusion
In 11 rabbits in which a histopathologic examination of the mediastinal mass was performed, the mass was identified as a thymoma. The thymomas were graded as a lymphocyte predominant type (n=6), a mixed lymphoepithelial type (n=4), and an epithelial predominant type (n=1). Cytokeratin expression was immunohistochemically detected in all specimens tested (n=6). In eight cases, cytology and histology were available and histologic results confirmed the diagnosis of thymoma by cytologic methods. Additional postmortem findings in nine rabbits included pleural effusion (n=6) and pericardial effusion (n=3) (Table 4).
Therapy and Outcome
In seven rabbits the thymomas were removed surgically. Two patients were treated conservatively, and the remaining four were euthanized at the owner's request due to their poor clinical condition (Table 1).
Anesthesia and Thoracotomy
All rabbits undergoing surgery were premedicated with 0.2 mg/kg medetomidine and 5–6 mg/kg ketamineg IM. Anesthesia was induced with IV propofolh. The trachea was intubated with a cuffed endotracheal tube (internal diameter was 2–2.5 mm), and anesthesia was maintained with a combination of IV propofol (11 mg/kg/hr) and remifentanili (10–20 μg/kg/hr). Once the thoracic cavity was opened, the lungs were manually ventilated with a tidal volume of 10–15 mL and a peak pressure of 10 cm H2O. Additionally, the rabbits received 5 mg/kg carprofenj IV and 0.03 mg/kg buprenorphinek IV during anesthesia and the postoperative period. A combination of lactated Ringer's solution, hydroxylethyl starchl, and 5% glucose (i.e., 60% lactated Ringer`s solution, 30% hydroxylethyl starch, and 10% glucose) was administered IV at 10 mL/kg/hr. Anesthetic depth and physiologic parameters, such as heart rate and rhythm (via an electrocardiogram), blood pressure (noninvasive oscillometric cuff), partial oxygen saturation, end-tidal carbon dioxide, and anesthetic gas concentrations (mainstream spirometry) were monitored closely throughout the procedure.
Thymoma excision was performed by subtotal to total median sternotomy. In cases where the mass adhered to the pericardium, a partial pericardectomy was performed. The thymoma was removed either in its entirety or in fragments when the tissue was friable. An 8 French chest drain was placed and connected to a three-way tap. The chest drain was removed once air or fluid production was minimal. All rabbits received 10 mg/kg enrofloxacinm either subcutaneously or orally q 24 hr for 7–14 days.
Five rabbits died within 3 days of surgery. One rabbit improved after surgery but had a recurrence of thymoma 6 mo later and was euthanized. One rabbit recovered completely after surgery but was euthanized 955 days following surgery because of a recurrence of the mediastinal mass (Table 1).
Conservative Treatment
Larger cystic lesions within the thymoma were aspirated in two rabbits under sedation with 1 mg/kg midazolam and 0.2 mg/kg medetomidine administered IM. One rabbit was also treated with oral prednisolonen at a dose of 0.5 mg/kg q 48 hr for 90 days. Rabbits that received conservative treatment survived for 5 mo and 9 mo (Table 1).
Discussion
According to the literature, mediastinal masses in rabbits are composed of thymic lymphomas and thymomas.15 Some authors have reported that thymomas are uncommon in rabbits; however, the current study revealed a thymoma in 13 rabbits over a period of 3 yr, indicating that mediastinal masses in rabbits consist primarily of thymomas rather than thymic lymphomas.8,9 This study indicates that thymomas appear to be more common than previously reported.
The rabbits in the current study were of comparable age (median age was 6.1 yr; range, 3–10 yr) to those reported in several other investigations, in which thymomas were found in rabbits 5–10 yr old.8,10,11 Only one rabbit in the current study was <4.5 yr.
The current study did not show any breed predilection for thymomas. To the authors’ knowledge there have been no investigations of breed predisposition for thymomas in rabbits.
In the current study, dyspnea was observed in approximately 75% of the rabbits with thymomas. There are numerous causes of dyspnea in rabbits, including upper respiratory disease (e.g., pasteurellosis, oronasal fistula following periapical abscess, foreign bodies, myxomatosis), lower respiratory disease (e.g., bronchopneumonia, pulmonary hemorrhage, pulmonary metastases from uterine or mammary carcinomas, pulmonary edema) as well as cases that relate to nonrespiratory reasons (e.g., pleural effusion, pneumothorax, diaphragmatic hernia, abdominal distension, metabolic disease).15,16However thymomas are often neglected.
Bilateral exophthalmos and bilateral prolapse of the third eyelid were observed in almost 50% and 25% of the rabbits, respectively. These results are consistent with other reports in which bilateral exophthalmos is commonly mentioned.4,6,10,11,15 Occasionally, bilateral exophthalmos in rabbits was transient and stress-induced and the condition was therefore either often undetected or misinterpreted by the referring veterinarians. According to previous publications, exophthalmos in rabbits is consistent with cranial vena cava syndrome due to a space-occupying mass that compresses the vessels of the thorax and restricts vascular return to the heart.7 Therefore, measurements of intraocular pressures to rule out buphthalmia were not performed in the six rabbits with bilateral exophthalmos as the condition was solely attributed to a cranial vena cava syndrome. Differential diagnoses for unilateral exophthalmos in rabbits mainly include retrobulbar abscesses due to dental disease and retrobulbar lymphoma of the Harderian gland.17,18
Similarly to other reports, the authors of this study did not notice anything remarkable or specific in the blood (hematology, serum biochemistry) of affected rabbits.10,11 Hypercalcemia, found as a paraneoplastic syndrome in dogs, was not detected in any of the four rabbits in which Ca levels were measured. Some authors discuss a connection between hypercalcemia and thymoma in rabbits; however, they fail to consider a possible influence of diet and Ca metabolism on the serum concentration of calcium in rabbits.5,6,15 In this study, the authors observed hyperglycemia in six rabbits, but assumed this to be stress-induced. Lymphocytosis associated with a thymoma that was detected in four rabbits and was previously reported in one dog.19
Methods for the diagnostic imaging of mediastinal masses in rabbits include radiographs, ultrasonography, and computed tomography (CT). Thoracic radiographs were helpful for visualizing a soft-tissue mass in the cranial mediastinum in conjunction with the characteristic elevation of the trachea. The dorsoventral plane was chosen instead of a ventrodorsal view as most rabbits were suffering from respiratory problems as a result of the thymoma.
Ultrasonography of the cranial mediastinal mass determined its echogenicity and extent. A small, high-frequency transducer should be used when attempting the intercostal approach. Because the masses occupied most of the cranial mediastinum, lung artifacts did not pose a problem and it was possible to place the rabbit in lateral recumbency. In accordance with one previous report, larger cystic lesions in the thymoma were detected in two rabbits, which were subsequently aspirated under ultrasound-guidance.10 Aspiration of these cysts is useful when the animal will not undergo surgery, as it alleviates the dyspnea.
CTs were not performed on any of the patients in this study as the diagnosis was confirmed by ultrasound-guided FNA. One author recommends CT of the thorax and the head to evaluate the extent of the mass and to eliminate the possibility of retrobulbar masses.10 Thoracic CT (including the application of IV contrast medium) may provide more information regarding the invasiveness of a cranial mediastinal mass and the presence of pulmonary metastasis. Although the application of a preoperative CT scan is useful, it can sometimes be difficult to determine the true extent of pleural and pericardial invasion.9 A greater number of patients will be required to evaluate whether a CT of the thorax is of diagnostic benefit in rabbits with thymomas.
Ultrasound-guided FNA of the cranial mediastinal mass led to the diagnosis in all cases but one, in which there were too few cells for an evaluation. In eight cases, cytology and histology were available and histologic results confirmed the diagnosis of thymoma by cytologic methods, giving a positive predictive value of 100%. Nevertheless, thymomas may be difficult to diagnose by cytology when a large number of lymphocytes are on the slide. In such cases, histology with staining for cytokeratin to detect epithelial cells is indicated to obtain a definitive diagnosis.1
Depending on the lymphocyte component, the thymomas could be classified as lymphocyte predominant (n=6), mixed lymphoepithelial (n=4) or epithelial predominant (n=1). In the six rabbits with a lymphocyte predominant type, immunohistochemical analysis of cytokeratin expression was used to confirm the diagnosis of thymoma because histologic differentiation between thymoma and thymic lymphoma is difficult. To the authors’ knowledge, this is the first time that thymomas in rabbits have been classified into subtypes, as described in dogs and cats. Whereas the lymphocyte predominant type of thymoma seems to occur more often in rabbits, the epithelial predominant type predominates in dogs and cats.2,20 Based on the results of the current study it is not possible to conclude whether the percentage of lymphocytes within thymomas has an influence on the survival time in rabbits, as has been documented in cats and dogs.2 Pathologic periocular findings (such as orbital abscesses, cysts, or neoplasms) were not found in the rabbits that underwent a postmortem examination, and no thoracic or abdominal metastases were detected on necropsy. There is only one report of renal metastases in a rabbit with thymoma.10 The authors of this work emphasize the risk of classifying a thymoma as benign following histology without considering thymic carcinoma and possible metastases. Several authors report that thymomas rarely give rise to metastases in any species.1,9,10,20 Furthermore, findings of the postmortem examination included pleural and pericardial effusion, which may have contributed to the dyspnea or cardiovascular problems in some rabbits.
To date there are only a few published reports on the treatment of thymomas in rabbits. The most common treatment options in rabbits are surgery and, with increasing frequency, radiation therapy.6,7,9,11,15 Recommendations for surgery or radiation therapy in rabbits depend on several factors such as concurrent diseases (e.g., cardiopulmonary disorders), the condition of the animal, the availability of a radiation treatment facility, and the owners’ wishes.9 Only 2/7 rabbits that underwent surgery were still alive 6 mo postsurgically. One rabbit had a recurrence of the thymoma 180 days after surgery and was euthanized. The other rabbit was euthanized >2.5 yr following surgery. In this case, thoracic radiographs revealed a mass in the cranial mediastinum. Therefore, a recurrence of thymoma was suspected, but could not be confirmed as cytology or histopathology was not available.
According to one report, perioperative death is the most common surgical complication.9 In the current study, five rabbits died within 3 days of surgery, largely as a result of acute respiratory distress. Some authors assume that perioperative death may be related to pain, stress, anesthesia complications, or the inability to remove the tumor.9 Thus, they strongly recommend intensive perioperative care (including placement of a chest tube and appropriate analgesia) and monitoring, as well as providing a low-stress environment for the rabbits. It has not been assessed whether placement of a chest tube in rabbits causes discomfort and consequently affects their clinical condition. Nevertheless, pleural and pericardial effusion and chronic inflammation of the epi- and pericardium were detected in the postmortem examination of five rabbits, which may have contributed to the animals’ postoperative death. In general, the survival time of rabbits that undergo sternotomy is strongly biased by the fact that patients with a poor clinical condition are excluded from invasive surgery because of a poor prognosis.
Radiation therapy is recommended after incomplete surgical resection of a thymoma or if a patient is not considered a good candidate for surgery. It is important to take possible side effects into account, such as pneumonitis, pulmonary fibrosis, and thrombosis of the thoracic vessels.9 The survival time in the cases reported ranged from 7 wk to 98 wk after the start of treatment, and one rabbit died during treatment.9,11,15 However, complications associated with irradiation of the lungs in rabbits have not yet been well documented.
One rabbit treated with aspiration of large cysts in the thymoma improved clinically, but died suddenly for unknown reasons 5 mo later. To date, the survival time after aspiration of thymic cysts has not been reported in rabbits, and there has been only one report of survival time of a rabbit with a thymoma that did not receive any treatment. That rabbit was euthanized 4 mo following diagnosis because of severe respiratory distress.4 In the current study, prednisolone was administered to one rabbit for a period of 90 days. The clinical signs disappeared for 270 days, after which time the animal was euthanized due to acute dyspnea. A necropsy was not performed. In one report, prednisolone (0.5–2 mg/kg orally q 12 hr) was successfully used as an adjuvant treatment in rabbits undergoing radiation therapy.9 However, radiation or steroid therapy (i.e., prednisolone) in rabbits may cause immunosuppression followed by the clinical manifestation of encephalitozoonosis.15
There is limited information regarding the efficacy of chemotherapy in rabbits as a treatment for metastatic or invasive thymomas or as supportive therapy in conjunction with surgery.9 One rabbit in the documented study collapsed after receiving chemotherapy.
Conclusion
Mediastinal masses often remain unrecognized in rabbits for a long period and should be considered as an important differential diagnosis in rabbits with respiratory distress and/or bilateral exophthalmos. This study found that mediastinal masses in rabbits consist primarily of thymomas rather than thymic lymphomas, and that they appear to be more common than previously reported. Cytology of samples collected by ultrasound-guided FNA give a good indication of the mass origin. Therefore, cytology is an accurate diagnostic tool to identify thymomas in rabbits. As surgical excision carries significant perioperative risk, intensive perioperative care is strongly recommended for a successful thoracotomy.
Thoracic radiographs of a rabbit in a lateral (A) and a dorsoventral (B) plane. There is a soft-tissue mass in the cranial mediastinum causing elevation of the trachea.
Ultrasonographic image of the mediastinal mass in a sagittal view. A large, hypoechoic, irregularly contoured mass (Th) is seen displacing the heart (H) caudally.
Ultrasonographic image of the cranial mediastinum in a sagittal view. A crescent-shaped, hypoechoic mass (Th) is seen cranial to the heart (H).
Cytology of a thymoma. Note the cluster of thymic epithelium (large white arrow) surrounded by a mixed population of large (thin white arrow) and small (black arrow) lymphocytes. The presence of a heterogeneous lymphocytic population differentiates thymomas from thymic lymphomas. Diff-Quick staining, original magnification ×400.
Contributor Notes
