Synovial T-Cell Lymphoma of the Stifle in a Dog

Case Report

A 6-year-old, 43-kg, spayed female rottweiler was examined by the Small Animal Orthopedic Service at Washington State University Veterinary Teaching Hospital for a 1-month history of progressive, left hind-limb lameness. She was currently being treated for a suspected cranial cruciate ligament rupture with cage rest and carprofen (2.2 mg/kg body weight, per os [PO], q 12 hours). Slight improvement of lameness was observed after initiation of this treatment plan. The owner also reported that the dog had urinary incontinence since being obtained as a puppy, and had repeated episodes of antibiotic-responsive bacterial urinary tract infections as an adult dog.

On presentation, the dog was nonweight-bearing on the left hind limb. Physical examination revealed a cranial drawer sign and palpable joint distention of the left stifle. The dog was sedated with butorphanol (0.2 mg/kg body weight, intravenously [IV]) and acepromazine (0.3 mg/kg body weight, IV) to obtain mediolateral and craniocaudal radiographs of the left stifle. Radiographically, the left stifle had evidence of moderate effusion, osteophyte formation on the distal aspect of the patella, periosteal proliferation on the cranial aspect of the distal femur, and mild enlargement of the popliteal lymph node [Figures 1A, 1B]. Initial examination findings were suggestive of a ruptured cranial cruciate ligament. Differential diagnoses included primary traumatic cranial cruciate ligament rupture or infectious and noninfectious causes of inflammatory joint disease with secondary cranial cruciate ligament pathology. A complete blood count (CBC), serum biochemical profile, and urinalysis were obtained in preparation for surgical exploration and stabilization of the left stifle. Hematological abnormalities included a mature neutrophilia of 10.5 × 10³/μL (reference range, 3.0 to 7.1 × 10³/μL), lymphopenia of 875/μL (reference range, 1.1 to 5.1 × 10³/μL), and monocytosis of 1.13 × 10³/μL (reference range, <800/μL). The packed cell volume (PCV) was 59% (reference range, 38% to 59%), and the hemoglobin was 20.5 g/dL (reference range, 13 to 19 g/dL). A thrombocytopenia of 100 × 10³ platelets/μL was noted (reference range, 157 to 394 × 10³/μL) with a mean platelet volume (MPV) of 12.3 μ³ (reference range, 6.5 to 9.9 μ³). Serum biochemical abnormalities included a mildly elevated alkaline phosphatase (ALP) of 92 IU/L (reference range, 14 to 72 IU/L), mild hypercholesterolemia of 395 mg/dL (reference range, 123 to 363 mg/dL), hyperglobulinemia of 4.1 g/dL (reference range, 2.7 to 3.8 g/dL), and an elevated serum creatinine of 2.1 mg/dL (reference range, 0.7 to 1.2 mg/dL). A urinalysis was obtained by cystocentesis. Results revealed a urine specific gravity (USG) of 1.010, 1+ proteinuria, and 1+ hemoglobinuria; a pH of 6.0 was identified by urine dipstick, and microscopic evaluation revealed an inactive sediment. Aerobic culture of urine did not yield microbial growth.

Azotemia in conjunction with isosthenuria indicated primary renal disease. Stifle surgery was postponed to pursue further diagnostic evaluation of the renal azotemia. Abdominal ultrasonography was performed. Both kidneys had multiple hyperechoic lesions involving the cortex and medulla. The margins of the left kidney were irregular. Corti-comedullary distinction was decreased, as the echogenicity of the medulla was similar to the cortex. Neoplasia, inflammation, fibrosis, or a combination of the above were considered potential causes for the abnormal renal architecture. A renal biopsy was recommended to elucidate the cellular composition of the hyperechoic regions. The owner was instructed to discontinue carprofen until the renal disease was controlled. The owner opted to return to the referring veterinarian for renal biopsy. The renal biopsy contained a small, cellular sample consisting of fibrosis, few tubular cells, and moderate pyogranulomatous inflammation.

Three weeks later, the dog returned to the Orthopedic Service at the Washington State University Veterinary Teaching Hospital for progression of the previously described lameness. The dog was being treated with amoxicillin (22 mg/kg body weight, PO, q 12 hours) for suspected chronic pyelonephritis, and carprofen at the previous dose and frequency. The owner perceived the dog was experiencing more pain. Due to the persistence of the lameness and progressive pain, the owner opted to pursue surgical exploration of the stifle despite the presence of renal disease.

Preoperative laboratory abnormalities included a more severe azotemia (blood urea nitrogen [BUN], 42 mg/dL; reference range, 9 to 27 mg/dL; creatinine, 3.5 mg/dL) and persistent isosthenuria (USG, 1.010). Thrombocytopenia was still present (87 × 10³ platelets/μL). The MPV had increased to 14.8 μ³. The PCV had increased to 64%. Serum cholesterol, globulin, and ALP were all within reference ranges. Results of the urinalysis obtained by cystocentesis were similar to results of the previous urinalysis, with a USG of 1.010, 1+ proteinuria, 2+ hemoglobinuria, a pH of 6.0, and an inactive sediment.

Despite worsening of renal disease and persistence of the thrombocytopenia, surgical intervention was pursued to identify the cause of the dog’s joint pain and provide surgical debridement and stabilization as indicated. A craniolateral approach to the stifle was taken. The cranial cruciate ligament was intact with no gross evidence of partial rupture. Qualitatively, the ligament appeared to have abnormal laxity when the stifle was placed in flexion. The synovium was markedly thickened. Synovial fluid and synovial biopsies were obtained, and the joint was lavaged. The joint capsule was closed routinely, and the biceps femoris fascia was closed in an imbricating pattern. Cytopathology of the synovial fluid revealed numerous well-preserved macrophages, two multi-nucleated cells resembling osteoclasts, synovial cells and lymphocytes in low numbers, and sparse neutrophils. This cytopathology was interpreted as a nonspecific, mixed-inflammatory response. The dog recovered uneventfully from surgery and was discharged pending biopsy results.

Histopathology of the synovium was characterized by large, densely cellular sheets of neoplastic lymphocytes invading the synovium [Figure 2]. Individual cells were round to polygonal, with scant, pale, basophilic cytoplasm, polymorphic nuclei, and large, often multiple nucleoli. Mitotic figures averaged 10 to 15 per 400× field. The neoplastic cells stained positively for a T-cell marker (i.e., CD3) and vimentin and negatively for a B-cell marker (i.e., CD79), confirming a diagnosis of diffuse, large-cell lymphoma (T-cell) of the synovium.

The dog returned to the Small Animal Internal Medicine Service at Washington State University Veterinary Teaching Hospital 3 weeks after surgery for lymphoma staging and treatment. At that time, the dog’s treatment consisted of amoxicillin and carprofen at the previously described doses and frequency. No new clinical signs had been noted by the owner; however, the dog had an episode of vomiting during the trip to the hospital. On physical examination, the stifle surgical site appeared to be healing without complications. No peripheral lymph-node enlargement was evident. Multiple, erythematous, raised, cutaneous nodules were found on the dorsum, head, and inguinal regions. Cytopathology of nodule aspirates was consistent with cutaneous lymphoma. The following morning, the dog had an episode of hematemesis. Carprofen was discontinued, and sucralfate (22 mg/kg body weight, PO, q 8 hours) and famotidine (0.5 mg/kg body weight, PO, q 24 hours) were administered. The dog continued to eat well until the third day of hospitalization when she became anorexic, lethargic, and febrile (103°F). New physical examination findings included abdominal distention and pain. Abdominocentesis yielded an opaque, brown fluid. Fluid analysis was consistent with an exudate (protein, 5.7 g/dL; 10,230 nucleated cells [97% degenerate neutrophils], and USG of 1.034). The owner elected euthanasia because of the rapid progression of clinical signs, the suspicion of septic peritonitis, and the severity of the underlying disease (i.e., T-cell lymphoma).

Necropsy confirmed peritonitis secondary to a perforated duodenal ulcer. Masses were found involving the bladder, urethra, spleen, lung, skin, both kidneys, and the musculature surrounding the left stifle. Histopathology confirmed infiltration of neoplastic lymphocytes at these sites and also identified microscopic infiltration of the bone marrow, stomach, popliteal and tracheobronchial lymph nodes, adrenal glands, and left stifle. Histopathology and immunohistochemistry confirmed the diagnosis of multicentric T-cell lymphoma.

Discussion

This case illustrates the importance of a thorough diagnostic evaluation in patients presenting for lameness. The radiographically identified lymph-node enlargement and blood-work abnormalities indicated that this dog either had a concurrent illness or an underlying disease causing her lameness and increased joint laxity. Neoplastic, infectious, and noninfectious inflammatory joint diseases were considered potential underlying causes for the clinical signs. Atypical presentations of neoplastic disease, such as were seen in this case, often lead to delayed diagnosis.

Lameness has been associated with a variety of primary musculoskeletal tumors. Distant-site tumors can also cause lameness, either because of synovial metastasis or a reactive synovitis.¹² Lymphoma of the synovium has previously been described in humans, cattle, a cat, and a sheep.^3–8 To the authors’ knowledge, this is the first case report of lameness associated with synovial lymphoma in a dog.

In domestic animals with synovial lymphoma, the stifle and the hock were the most common joints affected.⁷⁸ In human reports, the knee was the most commonly involved joint.^3–6 The sole presenting clinical sign was lameness or joint pain in all of these clinical cases.^3–8 Often no other lymph-node enlargement, hepatomegaly, or splenomegaly was noted on physical examination. This lack of systemic signs frequently led to misdiagnosis. Synovial lymphoma was often initially diagnosed as rheumatoid arthritis in human cases. Further diagnostic evaluation was necessary to suggest lymphoma as the cause of lameness. Definitive diagnosis was most consistently obtained by synovial biopsy in both human and domestic animal cases.^47–10

The clinical signs associated with lymphoma often reflect the affected organ system. T-cell lymphoma, in particular, can present for atypical signs due to unusual organ involvement.¹¹¹² Lymphoma has been reported in multiple locations, including lymph node, joints, intestine, stomach, spleen, liver, lung, eyes, skin, skeletal muscle, heart, central nervous system, and urethra.^211–16 The diffuse nature of lymphoma in this dog was initially underestimated because of the paucity of clinical signs. In retrospect, all the clinical signs and laboratory abnormalities could be attributed to lymphoma.

Neoplastic invasion of the synovium is known to cause lameness in humans and domestic animals. Positive cranial drawer sign with an intact cranial cruciate ligament may be the result of intrinsic ligament changes associated with inflammation of the joint.¹⁷¹⁸ Renal azotemia was likely a reflection of the extensive neoplastic infiltration of both kidneys and may have been exacerbated by the concurrent use of a nonsteroidal anti-inflammatory medication. Since neoplastic lymphocytes were not identified at the duodenal ulcer site, ulceration could have resulted from increased serum gastrin levels associated with renal failure,¹⁹ concurrent use of a nonsteroidal anti-inflammatory medication, or both. The polycythemia may be a reflection of increased erythropoietin production associated with renal neoplasms.²⁰ Based on the elevated MPV, the thrombocytopenia may have had an immune-mediated component. Clearly, this combination of blood-work abnormalities suggested an underlying systemic disease such as lymphoma. However, histopathology or an affected site was necessary to obtain a definitive diagnosis. The disparity between the ultrasound-guided renal biopsy and postmortem renal biopsy is likely a reflection of the small sample size of the initial biopsy.

Identification of neoplastic synovial infiltrate may require aggressive diagnostic evaluation. Cytopathological analysis of the synovial fluid may be helpful when neoplastic cells are identified; however, its sensitivity is likely low.²¹ Similar to human case reports, this rottweiler had a nonspecific inflammatory response within the joint, based on joint fluid cytopathology, but a definitive diagnosis of lymphoma on biopsy.⁴⁵ A review of synovial biopsy and synovial fluid cytology in 21 cattle with lymphoma found that neoplastic lymphocytes were rarely encountered in synovial effusion, despite identification of neoplastic lymphocytes in the synovium in 25 of 48 joints evaluated histologically.⁹¹⁰ A review of 27 cases of solid tumor metastasis to joints in humans reported neoplastic cells on joint fluid cytopathology in 50% of the patients, but histopathological evidence of neoplastic cells in 69% of the patients.²¹ Radiographic changes were variable in the human synovial lymphoma cases with interpretations that ranged from normal, to abnormalities of the soft tissue, bone, or both.^3–5 This dog and the previously described cat had evidence of bony remodeling on their radiographs.⁸ Even with normal radiographs and joint fluid cytopathology, a synovial biopsy is necessary to definitively rule out neoplastic infiltrate of the synovium.

Conclusion

Synovial lymphoma has been described in humans and multiple species of domestic animals. Neoplastic infiltration of any joint must be considered as a potential cause of lameness in patients with known lymphoma. In addition, lymphoma of the synovium should be considered as a differential diagnosis for progressive lameness in a mature animal when more common causes of lameness have been ruled out. A thorough diagnostic approach, including radiographs, cytopathology, and biopsy, is often necessary to identify lymphoma of the synovium.