Clinical and pathological findings of rabbits with lymphoma: 16 cases (1996–2019)

Jessica A. Robertson William R. Pritchard Veterinary Medical Teaching Hospital, School of Veterinary Medicine, University of California-Davis, Davis, CA

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David Sanchez-Migallon Guzman Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California-Davis, Davis, CA

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Jennifer L. Willcox Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California-Davis, Davis, CA

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Kevin Keel Department of Pathology, Microbiology and Immunology, School of Veterinary Medicine, University of California-Davis, Davis, CA

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William Vernau Department of Pathology, Microbiology and Immunology, School of Veterinary Medicine, University of California-Davis, Davis, CA

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Abstract

OBJECTIVE

To determine the clinical and pathological findings of rabbits diagnosed with lymphoma.

ANIMALS

16 rabbits.

PROCEDURES

The medical and pathology records database of the Veterinary Medical Teaching Hospital at the University of California, Davis was searched for rabbits diagnosed with lymphoma from 1996 to 2019.

RESULTS

Mean age of the 16 rabbits was 8 years (range, 4.5 to 12 years). Immunophenotyping was performed in 14 cases. Diffuse, large, B-cell lymphoma was most common (n = 7) followed by epitheliotropic, T-cell lymphoma (2); type II enteropathy-associated, T-cell lymphoma (2); marginal-zone, B-cell lymphoma (1); peripheral, T-cell lymphoma not otherwise specified (cutaneous nonepitheliotropic lymphoma; 1); primary, mediastinal (thymic) large B-cell lymphoma (1), and unclassified (cytology only with no immunophenotyping; 2). Multiple chemotherapy protocols were used on the basis of each individual animal’s disease state. Initial clinical improvement was reported for most rabbits receiving chemotherapy (5/6), with diffuse B-cell lymphoma responding most favorably to treatment. The 11 rabbits included in the survival analysis had a median survival time of 60 days (range, 1 to 480 days), and those diagnosed with B- and T-cell lymphoma had a median survival time of 8 and 36 days (range, 1 to 150 and 1 to 90 days), respectively.

CLINICAL RELEVANCE

Rabbits develop a range of lymphoma subtypes and, similar to humans and dogs, diffuse large B-cell lymphoma appears to be the most common. Chemotherapy treatments followed multiple protocols, which were mostly well tolerated and had a highly variable response. Further research into chemotherapy protocols is needed to optimize treatment of lymphoma in rabbits.

Abstract

OBJECTIVE

To determine the clinical and pathological findings of rabbits diagnosed with lymphoma.

ANIMALS

16 rabbits.

PROCEDURES

The medical and pathology records database of the Veterinary Medical Teaching Hospital at the University of California, Davis was searched for rabbits diagnosed with lymphoma from 1996 to 2019.

RESULTS

Mean age of the 16 rabbits was 8 years (range, 4.5 to 12 years). Immunophenotyping was performed in 14 cases. Diffuse, large, B-cell lymphoma was most common (n = 7) followed by epitheliotropic, T-cell lymphoma (2); type II enteropathy-associated, T-cell lymphoma (2); marginal-zone, B-cell lymphoma (1); peripheral, T-cell lymphoma not otherwise specified (cutaneous nonepitheliotropic lymphoma; 1); primary, mediastinal (thymic) large B-cell lymphoma (1), and unclassified (cytology only with no immunophenotyping; 2). Multiple chemotherapy protocols were used on the basis of each individual animal’s disease state. Initial clinical improvement was reported for most rabbits receiving chemotherapy (5/6), with diffuse B-cell lymphoma responding most favorably to treatment. The 11 rabbits included in the survival analysis had a median survival time of 60 days (range, 1 to 480 days), and those diagnosed with B- and T-cell lymphoma had a median survival time of 8 and 36 days (range, 1 to 150 and 1 to 90 days), respectively.

CLINICAL RELEVANCE

Rabbits develop a range of lymphoma subtypes and, similar to humans and dogs, diffuse large B-cell lymphoma appears to be the most common. Chemotherapy treatments followed multiple protocols, which were mostly well tolerated and had a highly variable response. Further research into chemotherapy protocols is needed to optimize treatment of lymphoma in rabbits.

Introduction

Lymphoid malignancy, including lymphoma and lymphocytic leukemias, is the second most common type of neoplasia in domestic rabbits.1,2 It is the most frequently reported neoplasm of young or juvenile rabbits, with the majority of animals being < 2 years of age at the time of diagnosis.15 Despite this frequency, only a limited number of case reports3,69 have been published describing lymphoma in domestic rabbits. Lymphoma has been observed in a variety of rabbit breeds including New Zealand white rabbits, English rabbits, Japanese white rabbits, and Dutch dwarf rabbits. It has also been diagnosed in wild and research colony rabbits.2,4,6,10

Classification of lymphoma in both veterinary and human medicine is complex and incorporates both clinical and morphologic features such as anatomic localization (multicentric, thymic, alimentary, cutaneous, or single organ involvement), architecture (diffuse or nodular masses), degree of differentiation (poorly or well differentiated), cytomorphology, and immunophenotype.1114 Lymphomas of both B-cell and T-cell origin have been described in domestic rabbits and lymphoma has been found in nearly all organs, including the lymph nodes, spleen, liver, gastrointestinal lymphoid tissue, kidney, skin, eye, and thymus.1,2,4,5 While systemic involvement is most commonly observed (liver, spleen, gastrointestinal tract, and lymph node),1,4,9,10,1517 localized forms, namely ocular18 and cutaneous,3,19 have also been described. Early publications described cases of lymphoma as being uniformly aleukemic in rabbits; however, more recent literature3 has also described a leukemia associated with multiple organ system involvement. There have also been reports3,2022 of chronic lymphocytic, acute lymphoblastic, and myeloid leukemia in rabbits.

The clinical manifestations of lymphoma in the domestic rabbit are variable and generally correspond with the organ system affected. Clinical signs are commonly nonspecific and constitutional in nature, including anorexia, lethargy, weight loss, and obtundation.2 Physical examination findings in rabbits diagnosed with lymphoma can include peripheral lymphadenopathy and/or an enlarged liver, spleen, or kidneys.2 In cases of cutaneous lymphoma, lesions may appear as cutaneous nodules or plaques that may have ulceration, crusts, erythema, or alopecia.2,3,23 In contrast, animals with mediastinal disease may be presented for bilateral exophthalmia with or without respiratory distress.2,8 Regardless of the presenting complaint, lymphoma in rabbits, as in other species, is often disseminated at the time of diagnosis.2,13

Despite the relatively common occurrence of lymphoma in rabbits, there is minimal information in the literature regarding presentation, diagnosis, therapy, and outcome. The objective of this study was to evaluate the clinical and pathological features of a cohort of client-owned rabbits diagnosed with lymphoma at a single institution. This case series was intended to add to the scant body of literature and facilitate the diagnosis and clinical management of rabbits with lymphoma.

Materials and Methods

Case selection—The medical and pathology record databases of the William R. Pritchard Veterinary Medical Teaching Hospital at the University of California-Davis was searched between January 1, 1996, and December 3, 2019, to identify rabbits with a cytologic or histopathologic diagnosis of lymphoma. Keywords used for the search included lymphoma and lymphosarcoma. Each case retrieved was reviewed by a single investigator (JR or DG). Captured information included signalment, pertinent history, physical examination findings, staging diagnostic results, treatments for lymphoma, and outcome. When available, signalment information included age, sex, and breed. History evaluation included the presenting complaint, relevant history, and review of records from primary care veterinarians. Outcome information was collected by medical records review and communications with owners and primary care veterinarians. Cytology and histopathology slides were reviewed for confirmation of diagnosis by a single board-certified pathologist (WV) and for cases with histopathology and immunophenotyping (14/16), World Health Organization (WHO) lymphoma type determined. Immunohistochemistry was performed using antibodies versus cluster of differentiation (CD) 3, CD20 and CD79a, as described previously.24 No additional inclusion or exclusion criteria were set.

Statistical analysis

Survival time was calculated from the date of diagnosis to date of death from any cause. Rabbits diagnosed at necropsy or euthanized within 24 hours of the date of diagnosis without therapy of any kind (including supportive care) were excluded from outcome analysis. Rabbits that were treated with either chemotherapy or palliative supportive care were included in survival analysis. The Kaplan-Meier approach was used to estimate survival time, and survival was censored on the date of last contact if rabbits were lost to follow-up or alive at the time of manuscript completion. Descriptive survival estimates were calculated for categorical variables (immunophenotype [B-cell vs T-cell], grade [small to intermediate cell and low grade vs large cell and high grade], and cancer treatment [surgery, chemotherapy, or corticosteroids] vs supportive or no care). However, no statistical comparisons were made between groups due to small sample size.

Results

The medical records search identified 19 rabbits with suspected lymphoma, and of those, 12 qualified for inclusion based on confirmation of lymphoma on histopathology. Pathology records review revealed 5 additional rabbits that also qualified for inclusion into our analysis on thec basis of histopathologic diagnosis of lymphoma. One rabbit diagnosed with ocular lymphoma was excluded, as this case had been included in another report.18 In total, 16 rabbits qualified for inclusion in this study.

Patient signalment and presenting complaint

Individual patient characteristics were tabulated (Supplementary Table S1). Of the 16 rabbits evaluated, multiple breeds, ages, and sexes were represented, including New Zealand White (n = 3), unidentified lop-eared breeds (3), silver martin (1), Netherlands dwarf (1), Havana (1), unidentified rex breed (1), and other unidentified breeds (6). The age at presentation ranged from 4.5 to 12 years, with a mean age of 8 years. Distribution of ages included < 5 years (n = 1), 5 to 10 years (12), > 10 years (2), and unidentified age (1). The 1 rabbit with an unreported age was noted to be adult. Sex distribution included 4 spayed females, 9 castrated males, 2 sexually intact males. and 1 animal of unknown sex. Rabbits were presented for various reasons including hyporexia or anorexia (n = 9), lethargy (8), nonhealing cutaneous lesion (3), upper respiratory tract signs (1), respiratory distress (1), soft tissue abdominal mass noted by primary care veterinarian (2), forelimb paresis (1), and an incidental finding after the rabbit declined postoperatively (1). A history was unavailable in 4 cases.

Results of the diagnostic evaluations performed were tabulated by patient (Supplementary Table S2). A CBC (n = 8), plasma biochemistry panel (7), cytology (6), skin biopsies (3), and urinalysis (1) were performed in patients as part of their evaluation.

Physical examination findings

Of the 16 rabbits evaluated, palpable abdominal masses (n = 6) were the most common physical exam abnormality, followed by cutaneous ulcerations (3), nasal discharge with increased bronchovesicular sounds ( 2), obtundation (2), heart murmur (1), bilateral exophthalmia (1), decreased thoracic compliance (1), non–weight-wearing lameness in the right thoracic limb (1), and no abnormal examination findings (1). Other examination findings unrelated to lymphoma included dental disease (n = 2), head tilt (1), and cataract (1).

Hematologic and biochemical findings

Complete blood counts revealed anemia (n = 2) and evidence of inflammation (leukocytosis, heterophilia, monocytosis, thrombocytosis, and/or hyperfibrinogenemia) in 4 of 8 cases.25 Circulating abnormal lymphocytes (secondary leukemia) were noted in 3 of 8 cases. Case 1 had unclassified cells that were described as large lymphoid cells that had a moderate amount of medium to deep-blue cytoplasm and round to ovoid nuclei with a finely stippled chromatin pattern. Case 6 had unclassified cells on blood smear examination that were described as large, immature, atypical lymphocytes that had nuclei approximately 2 to 4 RBCs in diameter, with multiple, prominent nucleoli; finely stippled to clumped chromatin; round, indented, or convoluted, nuclear membranes; and a variable, often moderate, volume of medium blue cytoplasm that often contained fine punctate vacuoles. These neoplastic lymphocytes were interpreted as most indicative of a marked, leukemic phase of high-grade lymphoma. Case 15 had large immature lymphocytes with abnormal nuclei and nucleoli suggestive of the leukemic phase of lymphoma. No significant abnormalities were noted in most of the 7 cases in which plasma biochemistry panels performed, except for case 15 that had mild hyperchloremia, mild hypoglycemia, moderate hypoproteinemia, mild hypercholesterolemia, moderately elevated creatine kinase activity, and mildly elevated aspartate aminotransferase activity.25

Diagnostic imaging findings

Results of diagnostic imaging were tabulated (Supplementary Table S2). Whole-body radiography was performed in 8 of 16 rabbits. Six of 8 animals had abnormalities on thoracic radiographs, which included pulmonary nodules (case 2); bicavitary effusion with nodular appearance to the pulmonary parenchyma and a soft tissue mass within the abdomen (case 6); soft tissue masses associated with the tail, tarsus, and antebrachium that lacked bone involvement (case 9); bicavitary effusion with pulmonary infiltrates (case 11); left humeral fracture and atypical appearance of the humeral condyle for which a pathological fracture could not be ruled out (case 13); and a cranial mediastinal mass (case 15). Abdominal ultrasonography was performed in 9 of 16 animals. Ultrasound findings included enlargement of mesenteric lymph nodes (6/9) as the most notable abnormality, along with focal thickening of the gastrointestinal tract (small intestine and cecum) in 5 of 9 animals and splenomegaly with hypoechoic splenic lesions in 2 of 9 animals. Thoracic ultrasonography was performed in 1 rabbit (case 15) and revealed a cranial mediastinal mass with mediastinal lymphadenopathy and pleural effusion.

Cytologic findings

Cytology was performed for 6 of 16 rabbits, and it was diagnostic for large cell lymphoma in all samples submitted (6/6). Case 1 had a splenic aspirate. Case 2 had both an enlarged mesenteric lymph node and a facial swelling that was aspirated (Figure 1). Cases 4 and 5 both had aspirates of a mesenteric lymph node and intestinal masses. Case 6 had aspirates obtained from an abdominal mass and aspirates were obtained from a cranial mediastinal mass in case 15. In all instances, the samples consisted of a relatively monomorphic population of large, immature appearing lymphocytes that had high nucleus-to-cytoplasm ratios. Nuclei ranged from 12 to 24 μm (2 to 4 RBCs) in diameter with variably clumped to finely stippled chromatin, 1 to 4 variably prominent nucleoli, and a continuous rim of mid to deep blue cytoplasm. Mitotic figures were noted frequently in all aspirates. The thymic mass aspirate (case 15) also contained many binucleate and multinucleate variants and striking anisokaryosis.

Figure 1
Figure 1

Photograph of a 5-year-old female spayed rabbit (case 2) presented with right maxillary facial swelling and diagnosed with diffuse large B-cell lymphoma (DLBCL) and postmortem photograph (B) and photomicrographs (C through E) of diagnostic findings. B—The gastrointestinal tract has multiple masses throughout. C—A fine-needle aspirate from the right maxillary facial swelling shows a relatively monomorphic population of large lymphocytes with round nuclei approximately 14 to 20 µm in diameter, finely stippled chromatin, high nuclear-to-cytoplasmic ratios, and a thin continuous rim of deep-blue cytoplasm. Wright-Giemsa stain; bar = 10 µm. D—A markedly expanded population of neoplastic lymphocytes completely effaces the tissues. Nuclei are large and approximately 14 to 20 µm in diameter, often with multiple, prominent peripheralized nucleoli. Mitoses are common (arrows). H&E stain; bar = 10 µm. E—Immunohistochemical staining indicates that large, neoplastic lymphocytes have diffuse cytoplasmic cluster of differentiation (CD) 79a expression, indicative of B-cell lineage. Immunoperoxidase stain with red-brown reaction product and hematoxylin counterstain; bar = 10 µm.

Citation: Journal of the American Veterinary Medical Association 260, 9; 10.2460/javma.21.03.0122

Histologic evaluation and immunophenotyping

Histopathology and immunophenotyping were performed for 14 of 16 rabbits. This included skin biopsies in 3 rabbits, with a diagnosis of epitheliotropic T-cell lymphoma in 2 rabbits, while a single rabbit was diagnosed as nonepitheliotropic, large T-cell lymphoma. Necropsy was performed in 12 rabbits. Of the 14 cases immunophenotyped, there were 9 B-cell lymphomas and 5 T-cell lymphomas. These cases were further classified using the WHO lymphoma classification11,12 as diffuse, large B-cell lymphomas (DLBCL; n = 7; Figure 2); epitheliotropic, T-cell lymphomas (Figure 3); type II enteropathy-associated, T-cell lymphomas (EATCL; 2; Figure 4); splenic marginal-zone, B-cell lymphoma (MZL; 1; Figure 5); peripheral, T-cell lymphoma, not otherwise specified (a cutaneous nonepitheliotropic lymphoma; 1); and primary, mediastinal (thymic) large B-cell lymphoma (1; Figure 6). Of the 16 cases in total (2 cases with cytology only), 11 were large-cell lymphomas with nuclei > 2 RBCs in diameter and usually much larger (2.5 to 4 RBCs in diameter). One of the 16 cases was intermediate (nuclei approx. 1.5 to 2 RBCs in diameter), and 4 others were small, mature-cell lymphomas (nuclei < 1.5 RBCs in diameter). For the 4 cases in which both cytology and histopathology were performed, there was concordance of both the diagnosis (lymphoma) and cell type (large).

Figure 2
Figure 2

Lateral radiographic view of an adult castrated rabbit (case 11) with enteropathy-associated T-cell lymphoma type II (A) and photomicrographs of diagnostic findings (B and C). A—The rabbit had also a mucinous adenocarcinoma in the ileum and ileocecocolic junction, and the pulmonary infiltrates were identified as metastatic adenocarcinoma. B—A section of jejunum showing that the intestinal villi are massively expanded by a dense round cell infiltrate. H&E stain; bar = 250 µm. C—There is a relatively monomorphic population of small, mature-appearing lymphocytes that have nuclei approximately 6 to 9 µm in diameter, clumped chromatin, inapparent nucleoli, and high nuclear-to-cytoplasmic ratios. Mitoses are rare (none present in this field). H&E stain; bar = 10 µm. See Figure 1 for remainder of key.

Citation: Journal of the American Veterinary Medical Association 260, 9; 10.2460/javma.21.03.0122

Figure 3
Figure 3

Photographs of alopecia, hyperkeratosis, and erythema around the eyes, mouth, neck, abdomen, medial aspect of the legs, and perineal region in a 6-year-old castrated male rabbit (case 8) with epitheliotropic T-cell lymphoma (mycosis fungoides; A and B) and photomicrographs of diagnostic findings (C and D). C—Immunohistochemical staining shows an expanded population of dermal CD3-positive lymphocytes in a section of skin that also infiltrate heavily into the overlying epidermis. Immunoperoxidase stain with red-brown reaction product and hematoxylin counterstain; bar = 30 µm. D—Neoplastic lymphocytes are small, mature-appearing cells with round to angular nuclei approximately 7 to 10 µm in diameter with clumped chromatin and inconspicuous nucleoli. H&E stain; bar = 10 µm.

Citation: Journal of the American Veterinary Medical Association 260, 9; 10.2460/javma.21.03.0122

Figure 4
Figure 4

Photomicrographs of a section of spleen from a 7-year-old castrated male rabbit (case 13) with marginal zone lymphoma. A—There are numerous large, nodular white pulp expansions that also infiltrate into the surrounding red pulp. H&E stain; bar = 250 µm. B—Neoplastic lymphocytes in the nodular white pulp expansions have round nuclei approximately 9 to 12 µm in diameter, often with single, central prominent nucleoli (arrows). H&E stain; bar = 10 µm. C—Immunohistochemical staining shows that the nodular white pulp expansions and the red pulp infiltrate are CD79a positive, confirming the B-cell lineage of the marginal zone lymphoma. Immunoperoxidase stain with red-brown reaction product and hematoxylin counterstain; bar = 250 µm. See Figure 1 for remainder of key.

Citation: Journal of the American Veterinary Medical Association 260, 9; 10.2460/javma.21.03.0122

Figure 5
Figure 5

Various images of a 9-year-old castrated Havana rabbit (case 15) with primary mediastinal (thymic) large B-cell lymphoma A—The lateral radiographic view shows a thymic mass. There is a moderate volume of pleural fluid resulting in retraction of the lung margins, widening of the cranial mediastinum with dorsal elevation of the trachea, and a diffuse interstitial pulmonary pattern. B—A postmortem photograph of gross findings shows the heart slightly caudally displaced by a 3.5 X 3.5 X 1-cm firm, smooth, multinodular, mottled white to pale-tan mass. C—Photomicrograph of a section of the mass shows neoplastic lymphocytes with very large nuclei approximately 12 to 24 µm in diameter, often with multiple, large, prominent nucleoli (arrows). Binucleated variants were common. H&E stain; bar = 10 µm. D—Photomicrograph of an immunohistochemically stained section shows large, neoplastic lymphocytes with strong cytoplasmic CD79a expression, indicative of B-cell lineage and a diagnosis of primary mediastinal (thymic) large B-cell lymphoma. Immunoperoxidase stain with red-brown reaction product and hematoxylin counterstain; bar = 10 µm. See Figure 1 for remainder of key.

Citation: Journal of the American Veterinary Medical Association 260, 9; 10.2460/javma.21.03.0122

Figure 6
Figure 6

Kaplan-Meier survival curve estimating survival time of rabbits (n = 11) with lymphoma. Median survival time is 60 days. The hash marks represent censored rabbits (n = 2).

Citation: Journal of the American Veterinary Medical Association 260, 9; 10.2460/javma.21.03.0122

Treatment and outcomes

Patient treatment and outcomes were summarized (Supplementary Table S1). Nine rabbits received therapy beyond supportive care, including chemotherapy (n = 6), corticosteroid drugs alone (1), retinoid therapy (1), and surgery (1). Of the remaining 7 rabbits, 2 received supportive care that included IV fluid therapy alone in one case and antibiotics and IV fluids in the other case; 5 rabbits did not receive treatment and were euthanized or died at the time of diagnosis.

Three of the 7 rabbits diagnosed with DLBCL received chemotherapy. Case 2 underwent treatment for 5 months prior to euthanasia. Throughout the course of treatment, this rabbit was receiving prednisolone (0.5 mg/kg) and trimethoprim-sulfamethoxazole (30 mg/kg) orally, every 12 hours. Treatment included doxorubicin (1 mg/kg, IV) every 3 weeks, for a total of 4 treatments. Response was clinically significant; the facial mass markedly reduced in size, the palpable abdominal masses were more difficult to discern within the abdomen, and the previously noted pulmonary nodule resolved radiographically. At a recheck appointment 3 weeks after the fourth administration of doxorubicin, a heart murmur was appreciated; however, no further diagnostics were pursued to characterize the murmur. With the concern for potential exacerbation of underlying heart disease due to possible doxorubicin-related cardiac toxicity, an alternative chemotherapy drug was recommended. Therapy with lomustine (70 mg/m2) was elected, and it was administered orally at week 12. Due to lack of clinical improvement, l-asparginase (400 U/kg) was administered SC at week 14. At week 16, no response or clinical improvement was noted and at the time a dose of vinblastine (1.6 mg/m2, IV) was administered. Moderate leukopenia (2,610 cells/μL) with 1,258 heterophils/μL occurred approximately at week 17; the nadir occurred at week 18 (total WBC count, 1,906 cells/μL; heterophil count, 915 cells/μL). Approximately at week 21, the WBC count had recovered enough for the administration of a single dose of cyclophosphamide (200 mg/m2, IV). However, the animal’s status continued to decline, and the owner elected euthanasia. Necropsy confirmed DLBCL, which involved the right, maxillary, subcutaneous tissue; bilateral nasal cavities; spleen; omentum; jejunum; ileum; vermiform appendix; right, mandibular lymph node; pharyngeal lymph nodes; liver; pancreas; lung; and kidney. Case 4 received a single SC dose of l-asparaginase (400 U/kg), and 1 week after the treatment, no clinical improvement or response was noted. Vincristine (0.29 mg/m2, IV) was administered at that time. When presented for this visit, the rabbit was assessed to be moderately dehydrated with quiet mentation. It was kept in the hospital overnight and was noted to be progressively lethargic the following morning. Euthanasia was elected, and a necropsy confirmed DLBCL in the animal’s cecum, cecocolic lymph node, spleen, liver, jejunum, kidney, lungs, and bone marrow. Case 5 was treated for 4 months prior to euthanasia. l-asparaginase (400 U/kg) was administered SC at the time of lymphoma diagnosis. One week after the l-asparaginase, the patient was placed on a modified protocol of cyclophosphamide, doxorubicin, and prednisone; in this case, vinblastine was substituted for vincristine).26,27 The protocol consisted of vinblastine (1.6 mg/m2) given in week 2, cyclophosphamide (200 mg/m2, IV) given in week 3, another dose of vinblastine (1.6 mg/m2) in week 4, and doxorubicin (1 mg/kg, IV) administered in week 5, with weekly CBC rechecks. A CBC was performed in week 6, and a vascular access port in the jugular vein was placed in week 7. At week 8, vinblastine (1.6 mg/m2, IV) was administered; however, progressive enlargement of this rabbit’s abdominal mass was noted. Given the concern for progression of the disease and the lack of response to vinblastine, doxorubicin was administered IV at week 9. The abdominal mass continued to increase in size, and an additional rescue dose of l-asparaginase (400 U/kg, SC) was administered at week 11. At the following recheck at week 12, lomustine (70 mg/m2) was administered orally. The animal was rechecked weekly including CBCs and presented approximately 4 weeks after lomustine administration in lateral recumbency, and the owners elected euthanasia. The necropsy confirmed DLBCL involving the jejunum, proximal duodenum, mesenteric lymph nodes, cranial mediastinal lymph nodes, right adrenal gland, and lungs. The other 4 cases that were diagnosed with DLBCL were euthanized and did not receive specific treatment for lymphoma.

The 2 rabbits diagnosed with large-cell lymphoma via cytology alone were treated, but neither was immunophenotyped. Case 1 underwent treatment with multiple chemotherapeutic drugs for 16 months. l-asparaginase (400 U/kg, SC) was administered initially after diagnosis, followed 3 weeks later by lomustine (70 mg/m2) administered orally every 3 weeks for a total of 10 treatments (8 months). Intermittent hyporexia and lethargy remained, so an additional dose of l-asparaginase (400 U/kg, SC) was administered after the last dose of lomustine (8 months postdiagnosis). Six weeks after the rescue dose of l-asparaginase, doxorubicin (1.0 mg/kg) was administered IV every 3 weeks for 3 treatments. No additional staging or diagnostic evaluations were performed. Due to lack of further response and worsening of clinical signs, palliative therapy was implemented with prednisolone (0.5 mg/kg) for approximately 4 months, and the animal was lost to follow-up. Case 6 was treated with a single dose of l-asparaginase (400 U/kg, SC) after the diagnosis of large-cell lymphoma was made cytologically from an abdominal mass aspirate and thoracic and abdominal fluid evaluation. This rabbit was also prescribed prednisolone (0.5 mg/kg, PO), with recommendations for a 1-week follow-up for additional therapy. Unfortunately, this patient was lost to follow up after this single visit.

The 3 cases of cutaneous lymphoma (2 epitheliotropic, T-cell lymphomas, and a single, nonepitheliotropic, T-cell lymphoma) received different treatments. Case 7 was administered soriatane (Acitretin) after epitheliotropic, T-cell lymphoma was diagnosed via skin biopsies. The rabbit received approximately 2.7 mg of soriatane/kg every 24 hours; one 25-mg capsule was mixed with 3 mL of an unknown brand of apple juice, and 1 mL of the mixture was administered for a total dose of approximately 8.3 mg. Minimal clinical improvement was observed, and the rabbit was euthanized 2 months after the initial diagnosis, without a necropsy. Case 8 received prednisolone (0.5 mg/kg, PO, q 12 h), and the rabbit was found deceased by the owners 18 days after a diagnosis of epitheliotropic, T-cell lymphoma was made from biopsy samples of skin. No necropsy was performed. Case 9 received 1 dose of l-asparaginase (400 U/kg, SC) following histopathologic diagnosis of cutaneous, nonepitheliotropic, large T-cell lymphoma. There appeared to be an initial response with improved appetite 1 to 2 days after administration, and 8 days later, the owners elected to pursue a dose of lomustine (70 mg/m2, PO). A second dose of lomustine was administered 5 weeks after the initial dose by the primary care veterinarian. Approximately 1 month following the second dose of lomustine, the rabbit was presented for labored breathing and was noted to have progression of the cutaneous lymphoma as well as a new the mass in the pelvic region, which affected ambulation. It had also developed hyporexia by that time. The rabbit was discharged on hospice care that included meloxicam, trimethoprim-sulfamethoxazole, enrofloxacin, and tramadol. Five days later (5 months after initial diagnosis), it was presented deceased on arrival. Necropsy confirmed the diagnosis of nonepitheliotropic, T-cell lymphoma.

The rabbits ultimately diagnosed with EATCL type II (cases 11 and 14), marginal-zone B-cell lymphoma (case 13), and primary, mediastinal (thymic) large B-cell lymphoma (case 15) did not undergo treatment and were euthanized, with the exception of case 13 that decompensated clinically and died prior to any diagnostic evaluation being performed.

Survival analysis

Of the 16 rabbits in this study, 11 were included in a survival analysis. Five rabbits were excluded because their lymphoma was diagnosed at the time of necropsy, and no therapy was previously prescribed for this diagnosis. Two rabbits were lost to follow-up and were censored on survival analysis at 1 day and 480 days—the time of last contact. The overall median survival time for this population was 60 days (range, 1 to 480 days; Figure 6). Of the 5 evaluable rabbits with B-cell lymphoma, the median survival time was 8 days (range, 1 to 150 days); for those 4 evaluable cases with T-cell lymphoma, the median survival time was 36 days (range, 1 to 90 days). Of the 9 rabbits receiving treatment beyond supportive care, the median survival time was 90 days (range, 1 to 480 days). For the remaining 7 rabbits, only 1 fulfilled criteria for survival assessment and had a survival time of 1 day, with the other 6 having been diagnosed at necropsy.

Discussion

To the authors’ knowledge, this was the first study to describe the clinical features and phenotypic characteristics of a series of client-owned, domestic rabbits with lymphoma. Lymphoma has previously been reported in the literature as a disease of young or juvenile rabbits, with most animals being < 2 years of age at the time of diagnosis.13,28 More recently, a large retrospective study4 of neoplasia in rabbits indicated the highest incidence of lymphoma occurred in rabbits between 25 and 48 months of age; however, that did not appear to be true with the patients in the present study. The age at presentation in our case series ranged from 4.5 to 12 years, with a mean age of 8 years. This middle-age distribution is more consistent with age ranges for a diagnosis of lymphoma in both dogs and cats.2932

As expected, clinical signs varied based on the organ system affected at the time of diagnosis. Animals with DLBCL that affected the gastrointestinal tract, spleen, liver, and/or kidneys were typically presented with nonspecific signs of disease including hyporexia, anorexia, changes in behavior, lethargy, and changes in fecal production. These clinical signs are similar to what has been observed in dogs,33,34 cattle,35 cats,30,36 and horses37 diagnosed with diffuse (multicentric) lymphoma. Rabbits diagnosed with cutaneous forms of lymphoma (epitheliotropic and nonepitheliotropic) were typically presented with skin lesions that were nonresponsive to empirical therapy; therefore, it is appropriate in rabbits to biopsy cutaneous lesions (scaling, crusting, or erythematous lesions), especially if empirical treatment for bacterial, fungal, or parasitic infections have produced minimal improvement.3

A CBC identified atypical or unclassified cells on blood smear examination in 3 of 8 rabbits of the present study. In each instance, these cells were interpreted as probable evidence of the leukemic phase of lymphoma. Rabbits in this study had other CBC findings including anemia, thrombocytosis, and hyperfibrinogenemia. Concurrent anemia is common in animals with lymphoma and has been reported in dogs,32 horses,37,38 ferrets,39 and cats.30,33,36 Interestingly, thrombocytosis appears to occur more frequently in rabbits, as many other species with lymphoma develop thrombocytopenia.32,34,38,39 Dogs are an exception and can develop either thrombocytosis40 or thrombocytopenia.29,31 No major findings attributable to paraneoplastic syndrome were noted on plasma biochemistry panels of the rabbits discussed in this study. A common paraneoplastic finding in dogs and cats with lymphoma is hypercalcemia41,42; however, this was not appreciated in any of the rabbits in which plasma biochemistry was done. The causes of hypercalcemia of malignancy are variable, but several mechanisms are thought to exist.42 One mechanism is parathyroid-related peptide production by the tumor, which has the same action as parathyroid hormone, stimulating both osteoclastic bone resorption and increased calcium tubular resorption via the kidneys.41 Parathyroid-related peptide was not measured in any of these rabbits; however, the mechanism by which rabbits excrete calcium43 may play a role in their lack of development of hypercalcemia of malignancy.

Staging with thoracic radiographs and abdominal ultrasonography was performed in 8 and 9 rabbits, respectively. Six rabbits had evidence of various lymphoma-related abnormalities on thoracic radiographs including pulmonary nodules or infiltrates, pleural effusion, and a cranial mediastinal mass. Abdominal ultrasonography also identified lymphoma-related abnormalities including enlargement of mesenteric lymph nodes, focal thickening of the gastrointestinal tract, and splenomegaly. Ultrasound was also particularly useful in facilitating fine-needle aspiration to obtain diagnostic samples in 5 cases. In the cases of DLBCL, multiple organ systems including gastrointestinal tract, kidney, liver, spleen, adrenal gland, lymph nodes, and lung were affected. Previously reported cases of lymphoma in rabbits have been noted to have a predisposition for affecting hilar and mediastinal lymph nodes, spleen, liver, and kidneys.15,16

Immunophenotyping was performed for most of the rabbits (14/16) in the present study; 9 of those tests indicated B-cell (64%) and 5 indicated T-cell origin (36%). In a recent large retrospective study4 of neoplasia in rabbits, B-cell lymphoma accounted for 96% of the lymphomas. We found a higher percentage of T-cell lymphomas, but caution should be exercised given the small number of cases evaluated. Histopathologic subclassification of lymphoma in this study was based on the WHO classification scheme.11,12 This scheme is used for classification of lymphoma in people, and it is becoming the pervasive scheme used in veterinary medicine.11,12 This study recognized 6 different WHO lymphoma types in domestic rabbits: DLBCL; epitheliotropic, T-cell lymphoma; EATCL type II; MZL; peripheral, T-cell lymphoma not otherwise specified; and primary, mediastinal (thymic) large B-cell lymphoma. To our knowledge, this is the first report of EATCL type II, MZL and primary mediastinal large B-cell lymphoma in rabbits.

DLBCL was the most common form of lymphoma noted in this study, with 7 rabbits being diagnosed. This is consistent with the findings of a recent retrospective study4 of neoplasia in rabbits, and it is also the most common type of lymphoma in dogs.44 Treatment of canine DLBCL is typically a combination multiagent chemotherapy or cyclophosphamide, doxorubicin, and prednisone protocol, including l-asparaginase, vincristine, cyclophosphamide, doxorubicin, and/or prednisone.45 The rabbits in the present study were treated with multiple chemotherapy drugs similar to those used and reported for canine lymphoma. In some cases, the rabbits demonstrated a possible response with improvement or complete resolution of clinical signs following chemotherapy implementation. However, accurate assessment of response and outcome comparison for specific drugs or protocols is challenging with the multitude of approaches used and the retrospective nature of the study.

Three cases of cutaneous lymphoma were diagnosed in this study. While only 1 of 3 rabbits with cutaneous lymphoma were submitted for necropsy, in that specific case, the disease remained localized to the skin. However, previously reported cases of cutaneous lymphoma have been characterized by more systemic disease involvement, most commonly also affecting the lungs and lymph nodes.3 The gross appearance of these lesions are nonspecific and can be easily mistaken for other, more common skin diseases. Gross lesions in these cases included alopecia (n = 3) with hyperkeratosis and erythema (3) or palpable, cutaneous masses (1) that affected the entire body, but appeared to occur more commonly at the commissures of the lips (2), ventrum (2), pelvic region, and thoracic limbs (2). Therapy was variable for the 3 rabbits with cutaneous lymphoma in this study, and it included oral retinoids, oral prednisolone, and chemotherapy with lomustine. Survival times associated with the oral retinoid treatment and oral prednisolone therapy were 30 and 18 days, respectively. No adverse effects were noted secondary to these therapies, but the short survival times may have led to lack of ability to identify adverse effects. A previous case report3 described the use of oral retinoid treatment, but treatment in that case was discontinued after 2.5 weeks due to financial constraints. However, given that both cases had minimal response to oral retinoid therapy, a positive response to therapy in rabbits may be less likely to occur than previously reported in dogs46 and cats.47 Lomustine is a chemotherapeutic agent commonly employed for this form of lymphoma in dogs,48 but it was administered to only one of the study rabbits, which had a survival time of 90 days. As this study included only a limited number of cutaneous lymphomas with varied treatment approaches, it was difficult to conclude which interventions may provide benefit for rabbits with cutaneous lymphoma.

The 2 rabbits diagnosed with EATCL type II were both presented to emergency, and no therapy was implemented prior to the animals being euthanized. This EATCL type II has been described commonly in cats with a median survival of over 3 years when treated with the oral chemotherapy drugs chlorambucil and prednisolone.49 Given the critical clinical presentation (respiratory distress and obtundation) of both rabbits, the biological behavior and prognosis for this form of lymphoma in rabbits cannot be determined.

The single case of splenic MZL was identified incidentally at necropsy after postoperative complications from a forelimb amputation. MZL’s are lymphomas with distinctive architecture that consist of intermediate-sized B cells with nuclei that are 1.5 to 2 RBCs in diameter that often have a single, large, central prominent nucleolus. They are generally indolent.11 In dogs, MZL is typically diagnosed in a single lymph node (most commonly cervical or submandibular); these animals typically have no clinical signs except for the lymph node enlargement.11 The second form of MZL is isolated to the spleen, with slow spread to the surrounding abdominal lymph nodes.11 It is important to distinguish MZL from DLBCL. DLBCL involves large cells with a higher mitotic rate and more aggressive biological behavior.11,12 As this diagnosis was made by necropsy in a single rabbit, no conclusions could be made regarding the clinical presentation or outcome of this form of lymphoma in rabbits.

A single case of mediastinal (thymic) large B-cell lymphoma was identified on necropsy. This patient was presented for nonspecific clinical signs, and it was euthanized once cytology of the cranial mediastinal mass was determined to be consistent with large-cell lymphoma. Cranial mediastinal masses in rabbits are most often thymoma, which is a tumor derived from the epithelial components of the thymus with associated polyclonal T-cell proliferation. Thymomas are one of the most common tumors in rabbits, with a reported prevalence of approximately 2.5% of all rabbits necropsied.4,9,50 Thymic lymphomas are less common than thymomas in rabbits, and in other animal species are most often of T-cell type,39 so the thymic large B-cell lymphoma identified in this series is noteworthy.

There are scarce reports1,2,10 of treatment for lymphoma in rabbits; however, some extrapolation from protocols in other species have been made. Treatment protocol decisions should be made based on the individual rabbit, clinical disease, and owner goals. Other considerations when implementing a chemotherapy protocol in a rabbit is appropriate knowledge of the animal’s anatomy and physiology, the ability to reliably obtain venous access, and an understanding of rabbits’ sensitivity to glucocorticoids as an adjunctive therapy for lymphoma.2 However, glucocorticoid therapy was an integral component of the treatment protocols for rabbits in this series of cases, and it did not appear that these animals had significant adverse effects. Further evaluation would be needed to determine the optimal dose and frequency of administration. Adverse effects of the chemotherapy protocols were difficult to extrapolate in many cases due to the retrospective nature of this study. Case 2 developed a new heart murmur while receiving doxorubicin chemotherapy and histopathology at the time necropsy identified cardiac myocyte damage, which was thought to be secondary to chemotherapy administration. Nonetheless, cardiac disease was not determined to be the underlying cause of death. It is unknown whether this was secondary to doxorubicin administration, but cardiotoxicity has been described as a serious adverse effect of long-term doxorubicin administration in humans5155 and rabbits,5659 leading to cardiomyopathies and congestive heart failure. The other 2 animals that received doxorubicin were either lost to follow up (case 1) or had no evidence of cardiomyopathy (case 5) at necropsy. With this in mind, more study is required to determine if screening rabbits with an echocardiogram should occur prior to or during therapy with doxorubicin. Case 2 also developed leukopenia, secondary to vinblastine, that resolved on follow-up CBC. Most commonly reported adverse effects of vinblastine administration in cats are gastrointestinal signs (vomiting, diarrhea, or decreased to absent appetite) and myelosuppression.27 In dogs administered vinblastine, approximately 57.5% developed myelosuppression, and more dogs had gastrointestinal signs when administered vinblastine in comparison to doxorubicin.60

Prognosis at this time seems to be highly variable depending on the type and stage of lymphoma, and prognosis is difficult to determine due to minimal data on the described chemotherapy protocols in rabbits with lymphoma. In 1 study,36 cats with alimentary lymphoma treated with either vincristine, cyclophosphamide and prednisone, or with chlorambucil and prednisone, had a survival time of 2 to 2,120 days (median, 50 days). A portion of the animals (32%) achieved complete remission (median, 213 days) and a portion of them (61%) failed to respond to chemotherapy. In another study61 of alimentary lymphoma therapy, cats were treated with chlorambucil and prednisone; a modified, Madison-Wisconsin, multiagent protocol; or a combination of the 2 protocols. In that study,61 76% of the cats had complete remission with a median remission time of 18.9 months, and those animals that achieved remission had a longer overall survival time (19.3 months) than those cats that never achieved remission (4.1 months).

In dogs with lymphoma, the chemotherapy agent of choice is a doxorubicin-based, multidrug protocol.32 Most dogs are reported to achieve remission with a median remission time of 7 to 10 months and a median survival time of 10 to 14 months.32 It appears that rabbits with lymphoma may have a similar response to chemotherapy. However, we did not have data allowing determination of whether rabbits were in remission. Nonetheless, the progression of disease in case 2 and case 5, despite chemotherapy, led to the conclusion that remission was not reached because these rabbits had survival times of 150 and 120 days, respectively. Loss of follow-up in case 1 did not allow for accurate determination of the survival time; however, it is plausible that this animal could be considered in remission given the longer known survival period of at least 480 days.

Limitations of the study reported here included a small number of cases and challenges associated with its retrospective nature, such as incomplete medical records in some instances, variation in case management, and loss to follow-up. The lack of a complete medical record in all instances makes progression of disease, response to therapies, and treatment-related adverse effects challenging to characterize. Other types of lymphoma reported in rabbits that are not part of this review include ocular lymphoma.18 A previous case series18 of ocular lymphoma in rabbits described ocular lymphoma following lens capsule rupture. This is similar to the round-cell variant of posttraumatic sarcomas previously described in cats, dogs, and rabbits, which is known to arise from any cause of lens rupture, including surgical or long-term ocular inflammation.18,62,63 However, ocular lymphoma in rabbits is different from previously reported ocular sarcoma by virtue of the distinct round-cell morphology and immunohistochemistry results that indicate B-cell differentiation.18 In the previously reported case series,18 the long-term follow up and survival time (12 to 54 months), with confirmed diagnosis of ocular lymphoma, make a primary traumatic origin more likely than a disseminated form of lymphoma. However, in one of those ocular lymphoma cases, metastatic disease to a regional lymph node was described.

More studies are needed to collect more data to further characterize age of onset, potential breed, and sex predilection, as well as risk factors for development of lymphoma in rabbits. Additionally, more studies are needed to determine standard recommendations for diagnostic testing, the variety and frequency of the different WHO lymphoma subtypes that occur in rabbits, and statistical information regarding prognosis. Lastly, further studies are needed to develop standardized chemotherapy protocols for different lymphoma subtypes in rabbits, that maximize duration and quality of life, reduce clinical signs of disease, and limit side effects.

Supplementary Materials

Supplementary materials are posted online at the journal website: avmajournals.avma.org

Acknowledgments

No third-party funding or support was received in connection with this study or the writing or publication of the manuscript. The authors declare that there were no conflicts of interest.

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