History

A 2-year-old sexually intact male mixed-breed dog was evaluated because of signs of depressed mentation and occasional vomiting and large bowel diarrhea with mucus and frank blood of 1 month's duration. The dog also had anorexia of 3 days' duration. The dog's vaccination status was current, and it had no other notable medical history.

Clinical, Cytologic, and Gross Findings

On physical examination, the dog was lethargic; signs of depressed mentation, tachypnea (60 breaths/min), and tachycardia (160 beats/min) were noted. The dog had defecated soft feces admixed with mucus and frank blood in the clinic lobby. During blood sample collection, excessive bleeding occurred at venipuncture sites. A CBC revealed no abnormalities other than mild neutrophilia (11,703 cells/μL; reference range, 2,060 to 10,600 cells/μL). The automated platelet count was low (50,000 platelets/μL; reference range, 170,000 to 400,000 platelets/μL), but platelet clumps were present; the estimated platelet count was deemed adequate. Serum biochemical abnormalities included azotemia (BUN concentration, 95 mg/dL [reference range, 6 to 25 mg/dL]; creatinine concentration, 5.5 mg/dL [reference range, 0.5 to 1.6 mg/dL]), hypercalcemia (16.7 mg/dL; reference range, 8.9 to 11.4 mg/dL), and hyperphos phatemia (6.8 mg/dL; reference range, 2.5 to 6.0 mg/dL). Urine specific gravity was inappropriately low (1.008), but urinalysis findings were otherwise within reference limits.

Abdominal radiography and ultrasonography revealed bilateral renal enlargement and enlargement of mesenteric and iliac lymph nodes. Fine-needle aspirates of mesenteric lymph nodes, spleen, and liver were collected for cytologic examination (Figure 1). Results of cytologic examination of slides prepared from the fine-needle aspirates collected from the mesenteric lymph nodes were nondiagnostic because of excessive cell rupturing. Cytologically, extramedullary hematopoiesis was evident in samples from the spleen, but no other abnormal cell populations were detected. Fine-needle aspirates obtained from the liver were sanguineous and contained a moderate number of nucleated cells. The nucleated cells consisted of numerous clusters of mature, well-differentiated hepatocytes, and a large number of lymphoid cells that were mostly medium to large lymphocytes with scattered small lymphocytes. The larger lymphocytes had generally round nuclei that were 2 to 2.5 times as large as the diameter of an erythrocyte with dispersed chromatin and indistinct nucleoli. Cytoplasm was scant and deeply basophilic. Although the patient was azotemic and had bilateral renal enlargement, fine-needle aspirates were not collected from the kidneys because of the difficulty and risk of that procedure without heavy sedation or anesthesia.

View Full Size

Photomicrograph of a fine-needle aspirate sample of the liver (A) and photograph of the kidneys (B) in a dog that was evaluated because of signs of depressed mentation and occasional vomiting and large bowel diarrhea with mucus and frank blood of 1 month's duration and anorexia of 3 days' duration. In panel A, a small cluster of hepatocytes is present in the upper left portion of the image, and a population of discrete cells is visible. Aqueous Romanowsky stain; bar = 20 μm. In panel B, the cortices of both kidneys contain multifocal to coalescing tan nodules of various sizes that have distorted the contour of the kidneys and replaced renal parenchyma.

Citation: Journal of the American Veterinary Medical Association 238, 2; 10.2460/javma.238.2.167

• Download Figure
• Download figure as PowerPoint slide

Because of the worsening clinical condition and poor prognosis for recovery, the dog was euthanatized and a necropsy was performed. Grossly, both kidneys were distorted by well-demarcated, multifocal to coalescing, and variably sized pale tan nodules (Figure 1). The liver had an enhanced lobular pattern and was mildly friable. Mesenteric and iliac lymph nodes were only slightly enlarged and had distinct corticomedullary architecture.

Formulate differential diagnoses from the history, cytologic and clinical findings, and Figure 1—then turn the page →

Histopathologic Findings

Samples of the liver, kidneys, spleen, stomach wall, small intestine, mesenteric lymph nodes, lungs, and bone marrow were collected during necropsy examination. Microscopic examination of tissues revealed diffuse sheets of neoplastic lymphocytes that infiltrated the cortical interstitium of the kidneys (Figure 2) as well as the connective tissue of portal and centrilobular regions of the liver. Similar neoplastic cells were present in bone marrow specimens. The mitotic rate was relatively high (5 mitotic figures/hpf). In all these samples, the neoplastic lymphocytes were immunohistochemically positive for CD3 (T-lymphocyte marker; Figure 3) and negative for CD79a (B-lymphocyte marker). Other notable microscopic lesions included mineralization of the alveolar septa, pulmonary vessel walls, bronchiolar basement membranes, and epithelium within the lung; mineralization, inflammation, and erosion within the gastric mucosa; mineralization and necrosis within the muscular layer of the stomach wall; and mineralization of tubular epithelium and basement membranes within the kidneys. Despite the history of diarrhea and hematochezia, there was no evidence of neoplasia in representative sections obtained from the dog's gastrointestinal tract, including portions of the stomach, small intestine, and colon. However, mild, segmental lymphoplasmacytic enteritis with neutrophilic inflammation in scattered crypts was detected in sections of jejunum and could have been associated with uremia. Sections of lymph nodes and spleen also lacked neoplastic infiltration.

View Full Size

Photomicrograph of a section of a kidney from the dog in Figure 1. Notice the sheets of numerous neoplastic lymphocytes that expand between renal tubules and glomeruli. Basement membranes of renal tubules are often segmentally or circumferentially mineralized and basophilic (arrowheads). H&E stain; bar = 75 μm.

Citation: Journal of the American Veterinary Medical Association 238, 2; 10.2460/javma.238.2.167

• Download Figure
• Download figure as PowerPoint slide

View Full Size

Photomicrograph of a section from the same kidney as shown in Figure 2 following immunohistochemical staining to detect CD3. Neoplastic lymphocytes that expand the interstitium between renal tubules have strong and specific intracytoplasmic and membranous staining for CD3, which indicates that the cells are of T-lymphocyte origin. Immunohistochemical stain specific for CD3; bar = 50 μm.

Citation: Journal of the American Veterinary Medical Association 238, 2; 10.2460/javma.238.2.167

• Download Figure
• Download figure as PowerPoint slide

Morphologic Diagnosis

Lymphoma of the kidneys, liver, and bone marrow (T-lymphocyte origin) and widespread soft tissue mineralization of the lung, stomach (with gastric mucosal erosion and mural myonecrosis), and kidneys (with renal tubular epithelial necrosis).

Comments

Lymphoma is one of the most common neoplasms of domestic animals. The multicentric form of lymphoma, with symmetric involvement of peripheral lymph nodes and other organs or tissues (including liver, spleen, tonsils, cranial mediastinum, and other organs) is the most common distribution pattern in dogs; alimentary, thymic, and cutaneous types follow in decreasing order of frequency.¹ Solitary lymphoma, in which the neoplasm is confined to 1 site, develops rarely in dogs but may involve the eyes, kidneys, CNS, or other organs.¹ In dogs, renal involvement in multicentric lymphoma is common; however, primary or solitary renal lymphoma is considered to be uncommon, although there are a few reports.^1–4 Despite extensive renal effacement without detectable lymph node involvement, the presence of neoplastic lymphocytes in liver and bone marrow makes a presumptive diagnosis of primary renal lymphoma equivocal at best. In some dogs with lymphoma, origin in the kidney cannot be definitively proven despite evidence supporting primary renal involvement of the neoplasm.^3,4 Therefore, the dog of this report could just as likely have had multicentric lymphoma with secondary renal infiltration.

Most (approx 70%) lymphomas in dogs are of B-lymphocyte origin; the frequency of T-cell lymphomas ranges from 10% to 40% of cases, and a small percentage (approx 2%) of lymphomas are the null-cell type (which lack both B-cell and T-cell markers).¹ Of 5 reported cases of renal lymphoma in dogs, the neoplastic cells were of T-lymphocyte origin in 2^5,6; the immunophenotype of neoplastic lymphocytes was not reported in other cases of renal lymphoma.^3,4,7 Dogs with T-cell lymphomas may be at greater risk of relapse following treatment and remission and have a poorer long-term prognosis than dogs with B-cell lymphomas.^1,8 Furthermore, in a report⁹ of T-cell lymphoma in 46 dogs, 16 (34.8%) were reported to have hypercalcemia.

Potential causes of hypercalcemia in dogs include primary hyperparathyroidism, hypercalcemia of malignancy (pseudohyperparathyroidism), hypervitaminosis D, adrenal gland insufficiency, lytic bone disease, and granulomatous inflammatory disease.¹⁰ In the dog of this report, pseudohyperparathyroidism associated with lymphoma was suspected. Pseudohyperparathyroidism, resulting from the production of parathyroid hormone-related protein by neoplastic cells,¹¹ is a common paraneoplastic syndrome in dogs with lymphoma and is most frequently associated with lymphoma of T-cell origin.⁸ Samples of serum were submitted to determine the concentrations of intact parathyroid hormone and parathyroid hormone—related protein in an attempt to confirm the cause of the hypercalcemia in the dog of this report; however, those test results were not available until after tissue samples were evaluated and a diagnosis had been made. The plasma concentration of parathyroid hormone—related protein was high (2.8 pmol/L; reference range, 0 to 1.0 pmol/L), which supported pseudohyperparathyroidism as the cause of hypercalcemia. Plasma concentration of intact parathyroid hormone was low (8.9 pg/mL; reference range, 27 to 155 pg/mL), which was also consistent with pseudohyperparathyroidism and was likely attributable to suppression of parathyroid hormone secretion through negative feedback from the high serum calcium concentration.¹²

Soft tissue mineralization involving multiple organs can occur either as a result of hypercalcemia or as a consequence of renal failure and uremia.¹³ Distinction between the 2 causes can be unclear because hypercalcemia often results in mineralization of the kidneys, which may subsequently lead to renal failure. In the dog of this report, it seems likely that both pseudohyperparathyroidism and compromised renal function (due to extensive neoplastic infiltration of the kidneys) contributed to mineralization of the lungs, stomach, and kidneys. High BUN and serum creatinine concentrations and isosthenuria, which did not resolve with fluid administration, were indicative of renal failure that was likely caused by hypercalcemia, renal neoplasia, or both in this patient. Hyperphosphatemia was most likely a result of decreased glomerular filtration secondary to compromised renal function.

The dog's clinical signs of depressed mentation, vomiting, and diarrhea of 1 month's duration accompanied by recent onset of anorexia were presumed to be a result of renal failure and uremia. In uremic patients, anorexia and vomiting frequently develop as a result of uremic gastroenteritis as well as effects of uremic toxins in the bloodstream.¹⁴ Uremic gastroenteritis, which is often hemorrhagic, typically results in melena rather than hematochezia because it develops in the proximal portion of the gastrointestinal tract. The mild nature of microscopic intestinal lesions in this dog may be attributable to their segmental rather than diffuse distribution within the gastrointestinal tract. Hemorrhagic diathesis, evidenced in the dog by excessive bleeding at venipuncture sites as well as bleeding within the gastrointestinal tract (which resulted in hematochezia), is another potential consequence of uremia that results from abnormal platelet function.¹⁴ Although liver failure can lead to a coagulopathy, the portal infiltrates of neoplastic cells in the dog's liver were not so extensive as to have affected hepatic function.