History
A 9-year-old 41-kg (90.2-lb) spayed female German Shepherd Dog was evaluated because of weight loss (2 kg [4.4 lb] over a 3-month period) and an 11-day history of polydipsia and polyuria. The dog had previously received intermittent treatment with stilbestrol for urinary incontinence and meloxicam for bilateral stifle joint osteoarthritis secondary to cranial cruciate ligament disease.
Clinical, Clinicopathologic, and Cytologic Findings
Physical examination revealed signs of mild discomfort on palpation over the kidneys. A CBC, serum biochemical analysis, and urinalysis revealed moderate leukocytosis (38.9 × 103 WBCs/μL; reference interval, 6 × 103 WBCs/μL to 17 × 103 WBCs/μL) characterized by moderate neutrophilia (33.84 × 103 neutrophils/μL; reference interval, 3 × 103 neutrophils/μL to 11.5 × 103 neutrophils/μL) and mild monocytosis (3.11 × 103 monocytes/μL; reference interval, 0.15 × 103 monocytes/μL to 1.35 × 103 monocytes/μL). Borderline hypercalcemia was present (serum total calcium concentration, 11.28 mg/dL; reference interval, 8.80 to 11.20 mg/dL), and the urine was isosthenuric (urine specific gravity, 1.008). Assessment of plasma electrolyte concentrations revealed mild ionized hypercalcemia (1.71 mmol/L; reference interval, 1.12 to 1.42 mmol/L).
Abdominal ultrasonography revealed dozens of hypoechoic to echogenic masses in the renal parenchyma, spleen, pancreas, and liver. Ultrasound-guided fine-needle aspiration of a renal mass yielded highly cellular samples composed of moderate numbers of large, individualized to loosely cohesive, round to polyhedral discrete cells with a high nuclear-to-cytoplasmic ratio, marked anisocytosis, and distinct cytoplasmic borders (Figure 1). The cells had a round nucleus, fine to clumped chromatin, inconspicuous nucleoli, and variable amounts of basophilic cytoplasm, which occasionally contained few fine, punctate vacuoles. Scattered mitotic figures were present, some with atypical morphology. There were also large numbers of bare nuclei, moderate numbers of small mature lymphocytes, and occasional intermediate and large lymphocytes on a pale proteinaceous background with a large number of free erythrocytes.
Photomicrograph of a fine-needle aspirate from a renal mass in a German Shepherd Dog that was evaluated because of weight loss over a 3-month period and an 11-day history of polydipsia and polyuria. Large individualized discrete cells and small mature lymphocytes are present in the preparation. Wright-Giemsa stain; bar = 10 μm.
Citation: Journal of the American Veterinary Medical Association 250, 4; 10.2460/javma.250.4.387
Formulate differential diagnoses from the history, clinical findings, and Figure 1—then turn the page→
Necropsy Findings
Euthanasia (by means of an IV overdose injection of pentobarbital) was elected, and a postmortem examination of the dog was performed. The cranial mediastinum was expanded by an approximately 16-cm-diameter, ovoid, soft, white-tan to red, lobulated mass that weighed 1.2 kg (2.7 lbs; 3% of body weight; Figure 2). Multiple adhesions to the lungs and diaphragm were present. Dozens of similar 0.5- to 3-cm-diameter masses were randomly distributed throughout the parietal pleura, lungs, liver, kidneys, pancreas, and spleen, and scattered nodules were present on the epicardial surface of the right ventricle and within the right gracilis muscle. Multiple samples of affected tissues and all other grossly normal organs were collected, immersed in neutral-buffered 10% formalin, and submitted for histologic examination.
Photograph of the thoracic cavity of the dog in Figure 1. A 16-cm-diameter, soft, lobulated mass is present in the cranial mediastinum.
Citation: Journal of the American Veterinary Medical Association 250, 4; 10.2460/javma.250.4.387
Histopathologic Findings
Consistent with cytologic findings in the renal mass, the cranial mediastinal mass was composed of large, round to polygonal cells arranged in densely cellular, loosely cohesive clusters and palisading cords intersected by a delicate fibrovascular stroma. Moderate numbers of small mature lymphocytes were interspersed throughout the mass (Figure 3). Neoplastic cells each had scant pale eosinophilic cytoplasm, a large round nucleus with lightly stippled chromatin, and variably distinct small nucleoli. Examination of several smaller masses revealed similar findings. Immunohistochemically, all neoplastic cells had strong cytoplasmic labeling for cytokeratin AE1/AE3; membranous immunolabeling for CD3 was present within infiltrating small mature lymphocytes.
Photomicrographs of sections of the cranial mediastinal mass and a renal lesion from the dog in Figure 1. A—Neoplastic cells are arranged into cords and clusters, interspersed with numerous small lymphocytes. H&E stain; bar = 10 μm. B—Numerous small, hyperchromatic lymphocytes have infiltrated between cords of neoplastic cells. The neoplastic cells are large and round to polygonal with scant cytoplasm and round nuclei with finely stippled chromatin. H&E stain; bar = 10 μm. C—Neoplastic cells, accompanied by abundant small lymphocytes, have infiltrated and replaced the renal cortical parenchyma. H&E stain; bar = 100 μm. D—In the mediastinal mass, strong cytoplasmic labeling for cytokeratin is present in all neoplastic cells. Cytokeratin-specific immunohistochemical stain; bar = 10 μm. E—In the mediastinal mass, many tumor-infiltrating T cells have strong membranous labeling for CD3. CD3-specific immunohistochemical reaction; bar = 10 μm.
Citation: Journal of the American Veterinary Medical Association 250, 4; 10.2460/javma.250.4.387
Morphologic Diagnosis and Case Summary
Morphologic diagnosis and case summary: metastatic lymphocyte-rich thymoma in a dog.
Comments
Gross and histologic findings in the present case were consistent with lymphocyte-rich thymoma and widely disseminated metastases. Thymomas are uncommon tumors in mammals and are derived from remnant thymic epithelial cells that persist within the cranial mediastinum following postnatal involution. A subset of thymomas is characterized by a nonneoplastic proliferation and infiltration of T lymphocytes in variable quantities; these thymomas are classified as lymphocyte rich.1 Thymomas are typically benign, although they may be locally infiltrative.2 Metastatic thymomas are rare but have been previously identified in a goat and several dogs.3–6
In dogs, the top differential diagnosis for a cranial mediastinal mass is thymic lymphoma. Other differential diagnoses in addition to thymoma include benign and malignant neoplasms of ectopic thyroid and parathyroid tissue, metastatic carcinoma, and chemodectoma as well as nonneoplastic processes such as thymic branchial cyst, lung lobe torsion, abscess, and granuloma.1,7 Definitive diagnosis requires histologic examination of sections of the mass, often with immunohistochemical testing. In the dog of the present report, histopathologic findings were most consistent with lymphocyte-rich thymoma, and strong labeling for cytokeratin excluded the differential diagnosis of T-cell-rich B-cell lymphoma. Lymphocyte-rich thymomas in which nonneoplastic T cells predominate pose a diagnostic dilemma and may be difficult to distinguish from thymic lymphoma.
Interestingly, no clinical signs referable to intrathoracic disease (eg, dyspnea or coughing) were reported for the dog of the present report. The primary signs—polyuria and polydipsia—were most likely attributable to paraneoplastic hypercalcemia, which induces nephrogenic diabetes insipidus via down-regulation of aquaporin-2 receptors in the distal renal tubules, resulting in polyuria8 for which polydipsia is compensatory. Paraneoplastic hypercalcemia is classically associated with T-cell lymphoma and anal sac adenocarcinoma in dogs but can develop with thymomas9 as well as many other neoplasms, most often because of the production of parathyroid hormone-related peptide by neoplastic cells.10 Definitive diagnosis of paraneoplastic hypercalcemia requires evaluation of circulating parathyroid hormone-related peptide concentration, which was not performed in the case described in the present report. Nevertheless, paraneoplastic hypercalcemia was favored as the cause of polyuria and polydipsia over differential diagnoses such as primary hyperparathyroidism, hypoadrenocorticism, secondary renal hyperparathyroidism, vitamin D toxicosis, and granulomatous disease, which were excluded on the basis of history and clinicopathologic, gross, and histopathologic findings. Full radiographic and postmortem examinations of the dog's bones were not performed; thus, osteolytic bone lesions cannot be entirely excluded. However, the dog had no lameness, signs of long bone pain, or high serum alkaline phosphatase activity to support osteolytic bone lesions as the cause of the hypercalcemia.
Myasthenia gravis is the most frequently reported paraneoplastic syndrome associated with thymoma in both dogs and people.11 In humans, myasthenia gravis is associated with a subset of lymphocyte-rich thymomas that contain large numbers of CD4+CD8+ T cells (World Health Organization type B1 and B2 tumors).12 The pathogenesis of thymoma-associated myasthenia gravis is incompletely understood but may be related to dysregulation of T-cell selection and formation of a T-cell population prone to autoreactivity.13 In humans, thymoma is also associated with a variety of other immune-mediated diseases and, similar to dogs, reported paraneoplastic syndromes include polymyositis, T-cell lymphocytosis, erythema multiforme, and hypercalcemia.14–16
Although rare in dogs, lymphocyte-rich thymoma should be considered as a differential diagnosis when cytologic examination of fine-needle aspirate specimens obtained from disseminated masses yield large individualized discrete cells admixed with a population of small mature lymphocytes, particularly if the presence of a cranial mediastinal mass has not been ruled out.
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